Compound having effect of promoting neuron differentiation

ABSTRACT

A novel cystacycline derivative which has an excellent effect of promoting the differentiation of neurons and is useful as a remedy for central nervous system disorders, a remedy for peripheral nerve disorders, etc.

TECHNICAL FIELD

The present invention relates to novel compounds having a neurondifferentiation promoting activity and pharmaceutical use thereof.

BACKGROUND ART

Neurotrophic factors are proteinaceous compounds that participate indifferentiation induction of neurons and in maintainance of theexistence and survival of nerve cells. Nerve growth factors (hereinafteroften abbreviated as NGF) are known to be representative of suchcompounds (Ann. Neuro., 10, 499-503 (1981)). It is manifested that NGFis deeply involved in the differentiation, existence maintenance andrepair of neurons in both the central and peripheral nervous systems.

Damages of nerves caused by aging, internal and external factors oftendevelop pathological symptoms. Such damages are found to cause, in thecentral nervous system, Alzheimer's disease, dementia induced bycerebro-vascular disorders, disturbance of consciousness due to cerebralcontusion, tremor or muscle rigidity by Parkinson's disease, etc. It isalso known that damages in the peripheral nervous system are induced byamyotrophic lateral sclerosis, spinal muscle atrophy, motor functiondisturbances due to neuron damages accompanied by accidents, etc., andthat neuropathies are induced by diabetes mellitus, uremia, vitamin B1or B12 deficiency , chronic liver disease, sarcoidosis, amyloidosis,hypothyrea, cancer, angiopathy, Sjögren symptoms, immunopathyaccompanied by infections, hereditary disease, physical compression,drugs (carcinostatic agents, tuberculostatic agents, anti-epilepticagents, etc.) or intoxication (arsenic, thallium, carbon disulfide,etc.); in more detail, see RINSHO KENSA (Clinical Test), 40, 760-766(1996). It was the recognition in the art that when neurons sufferirreversible damages from these disorders, it was difficult toregenerate and repair the damaged neurons. However, on the hypothesisthat neuropathy could be treated if the neurotrophic factors act onneurons, development of neurotrophic factors as medicaments againstneuropathy has been made. (Science, 264, 772-774 (1994)). For instance,clinical trial of NGF is in progress against Alzheimer's disease, neuraldamages or spinal injuries.

NGF is a series of proteins having approximately 50,000 molecularweight. For the treatment of neuropathy, it generally takes a longperiod of time. For these reasons, it is difficult to develop efficientadministration and pharmaceutical formulation. Gene therapy namelyinduction of NGF gene, is also another choice for the treatment but itstherapeutic effect is yet unclear.

It is known that when NGF is present, PC 12 cells—which are theestablished cell line cloned from rat adrenal medullapheochromocytoma—terminate cell proliferation and differentiate intoneuron-like cells with neurites. This procedure enables to screen aneffective substance having a NGF-like neuron differentiation promotingactivity. For example, antibiotic staurosporin was found to have the PC12 cell differentiation promoting activity (SHINKEI KAGAKU, 26, 200-220(1987)). A similar differentiation promoting activity was recentlyobserved in a biological active compound NK175203 (hereinafter referredto as cystacyclin) which was produced from Streptomyces sp. NK175203strain FERM BP-4372 (WO 95/31992).

However, the toxicity and pharmacokinetics of staurosporin m vivo makeits application as a medicament difficult. It has thus been stronglydesired to develop a low molecular weight compound that exhibits aneuron differentiation promoting activity, is low toxic and is readilyprepared synthetically.

DISCLOSURE OF INVENTION

The present inventors have made extensive investigations on cystacyclinederivatives and as a result, have found novel compounds represented bygeneral formulas [1A], [1B], [1C], [1D], [1E] and [1F] andpharmacologically acceptable salts thereof. The present invention hasthus been accomplished. The present invention relates to the followingcompounds and compositions comprising the same.

1) A cyclopentanone derivative represented by a formula [1A]:

wherein

X_(A) is O, S, SO, SO₂ or NH;

Y_(A) is a straight or branched aliphatic hydrocarbon group having 1 to20 carbon atoms, which may be substituted or unsubstituted, or asubstituted or unsubstituted aromatic hydrocarbon group or monocyclicaromatic heterocyclic ring having 3 to 6 carbon atoms;

each of Z1_(A), Z2_(A) and Z3_(A), which may be the same or differentand independently represents carboxy or a group derived therefrom, anunsubstituted or substituted alkyl having 1 to 4 carbon atoms, hydroxyor a group derived therefrom, amino or a group derived therefrom,sulfonate or a group derived therefrom, phosphate or a group derivedtherefrom, a monocyclic heteroaryl, a halogen or hydrogen; or Z2_(A) andZ3_(A) are combined together to form a substituted or unsubstitutedaromatic hydrocarbon or aromatic heterocyclic ring; and,

Z1_(A) is carboxy or a group derived therefrom, an unsubstituted orsubstituted alkyl having 1 to 4 carbon atoms, hydroxy or a group derivedtherefrom, amino or a group derived therefrom, a halogen or hydrogen,with the proviso that, when Z2_(A) and Z3_(A) are both hydrogen, Z1_(A)is hydroxy or a group derived therefrom, amino or a group derivedtherefrom, sulfonate or a monocyclic aromatic heterocyclic ring, ahalogen or hydrogen, and Y_(A) is a substituted or unsubstitutedstraight or branched aliphatic hydrocarbon group having 1 to 6 carbonatoms;

with the proviso that (1) through (7) are excluded:

(1) when Z1_(A) and Z2_(A) are hydrogen, X_(A) is S, Y_(A) is methyl orbenzyl and, Z3_(A) is methoxycarbonyl,

(2) when Z1_(A) and Z2_(A) are hydrogen, X_(A) is O or N, Y_(A) isbenzyl and, Z3_(A) is carboxy, methoxycarbonyl or ethoxycarbonyl;

(3) X_(A) is N or O, Z1_(A) and Z3_(A) are hydrogen and, Z2_(A) iscarboxy or methoxycarbonyl;

(4) X_(A) is O, Z1_(A) is hydroxy or a group derived therefrom, Z2_(A)is hydrogen and, Z3_(A) is amino or a group derived therefrom;

(5) X_(A) is S, Y1_(A) is phenyl, Z1_(A) is dimethoxymethyl and, Z2_(A)and Z3_(A) are hydrogen;

(6) X_(A) is O, Y1_(A) is methyl, Z1_(A) is is1-methoxy-1-phenylthiomethyl and, Z2_(A) and Z3_(A) are hydrogen;

(7) Z1_(A) is S, SO or SO₂, Z2_(A) is hydroxy or a group derivedtherefrom and, Z3_(A) is hydrogen;

or a pharmacologically acceptable salt thereof;

a 2,3-di-substituted cyclopentanone derivative of formula [1B]:

 wherein:

X_(B) is O, S, SO, SO₂ or NH;

Y_(B) is:

an unsubstituted or substituted straight or branched aliphatichydrocarbon group having 7 to 20 carbon atoms,

a straight or branched aliphatic hydrocarbon group having 1 to 6 carbonatoms, wherein:

at least one hydrogen is substituted with COW1 (wherein W1 is anunsubstituted or substituted aromatic heterocyclic ring or saturatedheterocyclic ring) and, at least one hydrogen may be further substitutedwith a group derived from amino; or,

at least one hydrogen is substituted with NHCOV1 (wherein V1 is an alkylhaving 2 to 5 carbon atoms containing 4 to 11 halogen atoms) and atleast one hydrogen may be further substituted with carboxy or a groupderived therefrom; or,

at least one hydrogen is substituted with a substituted or unsubstitutedmonocyclic aromatic heterocyclic ring and, at least one hydrogen may befurther substituted with amino or a group derived therefrom; or,

a substituted or unsubstituted aromatic hydrocarbon group or monocyclicaromatic heterocyclic ring having 3 to 6 carbon atoms;

Z_(B) is carboxy or a group derived therefrom, sulfonate or a groupderived therefrom, phosphate or a group derived therefrom, anunsubstituted or substituted alkyl having 1 to 4 carbon atoms, hydroxy,OR1 (wherein R1 is an unsubstituted or substituted alkyl having 1 to 4carbon atoms or, an unsubstituted or substituted acyl having 1 to 5carbon atoms), NHCOR2 (wherein R2 is an unsubstituted or substitutedalkyl having 1 to 4 carbon atoms), NHSO₂R2′ (wherein R2′ is anunsubstituted or substituted alkyl having 1 to 4 carbon atoms orphenyl), a monocyclic aromatic heterocyclic ring, a halogen or hydrogen;

or a pharmacologically acceptable salt thereof;

a cyclopentenone derivative of formula [1C]:

 wherein:

ring A has one double bond conjugated with oxo;

X_(c) is O, S, SO, SO₂ or NH;

Y_(c) is a substituted or unsubstituted aliphatic hydrocarbon grouphaving 1 to 6 carbon atoms or a substituted or unsubstituted aromatichydrocarbon group or monocyclic aromatic heterocyclic ring having 3 to 6carbon atoms;

each of Z1_(c), Z2_(c) and Z3_(c), which may be the same or differentand independently represents carboxy or a group derived therefrom,hydroxy or a group derived therefrom, amino or a group derivedtherefrom, a substituted or unsubstituted alkyl or alkenyl having 1 to 4carbon atoms, a monocyclic aromatic heterocyclic ring, a halogen atom orhydrogen;

with the proviso that, when X_(c) is O or NH, Z1_(c) and Z3_(c) are nothydrogen and, Z2_(c) is not hydrogen or, hydroxy or a group derivedtherefrom;

or a pharmacologically acceptable salt thereof;

a ketone derivative of formula [1D]:

 wherein:

A_(D) is an unsubstituted or substituted aliphatic hydrocarbon grouphaving 1 to 4 carbon atoms, an unsubstituted or substituted aromatichydrocarbon, heterocyclic ring or saturated heterocyclic ring;

B_(D) is hydrogen or an unsubstituted or substituted aliphatichydrocarbon group having 1 to 4 carbon atoms; or,

A_(D) and B_(D) are combined together to form an unsubstituted orsubstituted cycloalkan-1-one ring having 3 to 7 carbon atoms (except for5 carbon atoms);

X_(D) is O, S, SO, SO₂ or NH;

Y_(D) is a substituted or unsubstituted aliphatic hydrocarbon grouphaving 1 to 6 carbon atoms or a substituted or unsubstituted aromatichydrocarbon group or monocyclic aromatic heterocyclic ring having 3 to 6carbon atoms;

Z_(D) is carboxy or a group derived therefrom, an unsubstituted orsubstituted alkyl or alkenyl having 1 to 4 carbon atoms, hydroxy or agroup derived therefrom, amino or a group derived therefrom, sulfonateor a group derived therefrom or, phosphate or a group derived therefrom,a monocyclic aromatic heterocyclic ring, a halogen or hydrogen;

with the proviso that, when A_(D) and B_(D) are combined together toform a cyclobutane ring, the following (1) through (4) are excluded:

(1) X_(D) is O, Y_(D) is methyl, n-octyl or n-hexadecyl and, Z_(D) ismethoxycarbonyl;

(2) X_(D) is O, Y_(D) is benzyl and, Z_(D) is benzyloxylmethyl;

(3) X_(D) is O, Y_(D) is p-methoxybenzyl and, Z_(D) isp-methoxybenzyloxymethyl; and,

(4) X_(D) is O, Y_(D) is trityl and Z_(D) is trityloxymethyl or, whenA_(D) is an unsubstituted benzene ring and B_(D) is hydrogen, X_(D) isS, Y_(D) is methyl, ethyl or isopropyl and Z_(D) is carboxy;

or a pharmacologically acceptable salt thereof;

a compound of formula [1E]:

or a pharmacologically acceptable salt thereof; or,

a β-di-substituted aminoketone derivative of formula [1F]:

 wherein:

A_(F) is an unsubstituted or substituted aliphatic hydrocarbon grouphaving 1 to 4 carbon atoms or, an unsubstituted or substituted aromatichydrocarbon ring, aromatic heterocyclic ring or saturated heterocyclicring;

B_(F) is hydrogen or, an unsubstituted or substituted aliphatichydrocarbon group having 1 to 4 carbon atoms; or,

A_(F) and B_(F) are combined together to form an unsubstituted orsubstituted cycloalkan-1-one ring having 3 to 7 carbon atoms or, to forma cycloalkan-1-one ring having 3 to 7 carbon atoms and fused with anaromatic hydrocarbon or a aromatic heterocyclic ring;

each of X_(F) and Y_(F) is an unsubstituted or substituted straight orbranched aliphatic hydrocarbon group having 1 to 10 carbon atoms or,X_(F) and Y_(F) are bound to each other directly or via a hetero atom toform an unsubstituted or substituted heterocyclic ring;

Z_(F) is carboxy or a group derived therefrom, an unsubstituted orsubstituted alkyl or alkenyl having 1 to 4 carbon atoms, hydroxy or agroup derived therefrom, amino or a group derived therefrom, sulfonateor a group derived therefrom, phosphate or a group derived therefrom, amonocyclic aromatic heterocyclic ring or a halogen;

with the proviso that, when A_(F) is an unsubstituted benzene ring,excluded are those wherein B_(F) is hydrogen, X_(F) and Y_(F) are boundto each other directly to form a piperidine ring and, Z_(F) is carboxy;or a pharmacologically acceptable salt thereof.

2) A cyclopentanone derivative of formula [1A] or a pharmacologicallyacceptable salt thereof, according to 1) above, wherein:

X_(A) is S, O, S or SO;

Y_(A) is a straight or branched aliphatic hydrocarbon group having 1 to20 carbon atoms (wherein at least one hydrogen atom is substituted withcarboxy or a group derived therefrom, or amino or a group derivedtherefrom);

each of Z1_(A), Z2_(A) and Z3_(A), which may be the same or differentand independently represents carboxy or a group derived therefrom, anunsubstituted or substituted alkyl having 1 to 4 carbon atoms, hydroxyor a group derived therefrom, amino or a group derived therefrom, amonocyclic aromatic heterocyclic ring, a halogen or hydrogen; or Z2_(A)and Z3_(A) are combined together to form a substituted or unsubstitutedaromatic hydrocarbon or a aromatic heterocyclic ring; and,

Z1_(A) is carboxy or a group derived therefrom, an unsubstituted orsubstituted alkyl having 1 to 4 carbon atoms, hydroxy or a group derivedtherefrom, amino or a group derived therefrom, a halogen or hydrogen.

3) A cyclopentanone derivative of formula [1A] or a pharmacologicallyacceptable salt thereof, according to 2) described above, wherein:

X_(A) is S;

Y_(A) is a straight or branched aliphatic hydrocarbon group having 1 to6 carbon atoms, wherein;

at least one hydrogen atom is substituted with carboxy, COOR1 (whereinR1 is a substituted or unsubstituted alkyl, alkenyl or alkynyl having 1to 4 carbon atoms), COW1 (wherein W1 is a heterocyclic ringunsubstituted or substituted with carboxy or a group derived therefrom)or NR2R3 (wherein each of R2 and R3, which may be different or the sameindependently, represents hydrogen, an unsubstituted or substitutedalkyl having 1 to 4 carbon atoms or, an unsubstituted or substitutedacyl having 1 to 5 carbon atoms);

each of Z1_(A), Z2_(A) and Z3_(A), which may be the same or differentand independently represents carboxy, COOR4 (wherein R4 is anunsubstituted or substituted alkyl having 1 to 4 carbon atoms), CONR5R6(wherein each of R5 and R6, which may be different or the sameindependently, represents hydrogen or a substituted or unsubstitutedalkyl having 1 to 4 carbon atoms), cyano, hydroxy, OR7 (wherein R7 is anunsubstituted or substituted alkyl having 1 to 4 carbon atoms or, anunsubstituted or substituted acyl having 1 to 5 carbon atoms), NR8R9(wherein each of R8 and R9, which may be the same or different andindependently represents hydrogen, an unsubstituted or substituted alkylhaving 1 to 4 carbon atoms or, an unsubstituted or substituted acylhaving 1 to 5 carbon atoms), CH₂OR10 (wherein R10 is hydrogen, anunsubstituted or substituted alkyl having 1 to 4 carbon atoms or, anunsubstituted or substituted acyl having 1 to 5 carbon atoms), chlorine,fluorine or hydrogen; or,

Z2_(A) and Z3_(A) are combined together to form a substituted orunsubstituted aromatic hydrocarbon; and,

Z1_(A) is carboxy, COOR4 (wherein R4 is an unsubstituted or substitutedalkyl having 1 to 4 carbon atoms), CONR5R6 (wherein each of R5 and R6,which may be different or the same independently, represents hydrogen ora substituted or unsubstituted alkyl having 1 to 4 carbon atoms), cyano,hydroxy, OR7 (wherein R7 is an unsubstituted or substituted alkyl having1 to 4 carbon atoms or, an unsubstituted or substituted acyl having 1 to5 carbon atoms), NR8R9 (wherein each of R8 and R9 which may be the sameor different and independently represents hydrogen, an unsubstituted orsubstituted alkyl having 1 to 4 carbon atoms or, an unsubstituted orsubstituted acyl having 1 to 5 carbon atoms), CH₂OR10 (wherein R10 ishydrogen, an unsubstituted or substituted alkyl having 1 to 4 carbonatoms or, an unsubstituted or substituted acyl having 1 to 5 carbonatoms), chlorine, fluorine or hydrogen.

4) A cyclopentanone derivative of formula [1A] or a pharmacologicallyacceptable salt thereof, according to 3) described above, wherein:

X_(A) is S;

Y_(A) is a straight aliphatic hydrocarbon group having 1 to 6 carbonatoms, wherein:

at least two hydrogen atoms are substituted with any of carboxy, COOR1′(wherein R11 is an alkyl, alkenyl or alkynyl having 1 to 4 carbonatoms), COW2 (wherein W2 is a saturated heterocyclic ring unsubstitutedor substituted with COOR11 (wherein R11 is an alkyl having 1 to 4 carbonatoms) or NHCOR12 (wherein R12 is an alkyl having 1 to 4 carbon atoms);

each of Z1_(A), Z2_(A) and Z3_(A), which may be the same or differentand independently represents carboxy, COOR4′ (wherein R4′ is an alkylhaving 1 to 4 carbon atoms), hydroxy, OCOR13 (wherein R13 is an alkylhaving 1 to 4 carbon atoms), CH₂OR10′ (wherein R10′ is hydrogen, analkyl having 1 to 4 carbon atoms or an acyl having 1 to 5 carbon atoms),or hydrogen; or,

Z2_(A) and Z3_(A) are combined together to form a benzene ringunsubstituted or substituted with an alkyl having 1 to 4 carbon atoms,an alkyloxy having 1 to 4 carbon atoms, nitro, trifluoromethyl orhalogen; and,

Z1_(A) is carboxy, COOR4′ (wherein R4′ is an alkyl having 1 to 4 carbonatoms), hydroxy, OCOR13 (wherein R13 is an alkyl having 1 to 4 carbonatoms), CH₂OR10′ (wherein R10′ is hydrogen, an alkyl having 1 to 4carbon atoms or an acyl having 1 to 5 carbon atoms), or hydrogen.

5) A cyclopentanone derivative of formula [1A] or a pharmacologicallyacceptable salt thereof, according to 4) described above, wherein:

X_(A) is S;

Y_(A) is a straight aliphatic hydrocarbon group having 1 to 6 carbonatoms, wherein:

one hydrogen is substituted with carboxy, methoxycarbonyl, COW3 (whereinW3 is a pyrrolidine, piperidine, azetidine, morpholine or piperazinering, which may be unsubstituted or substituted with methoxycarbonyl)and one other hydrogen is substituted with acetylamino;

each of Z1_(A), Z2_(A) and Z3_(A), which may be the same or differentand independently represents carboxy, methoxycarbonyl, hydroxy,acetyloxymethyl, hydroxymethyl or hydrogen; or,

Z2_(A) and Z3_(A) are combined together to form unsubstituted benzenering; and,

Z1_(A) is carboxy, methoxycarbonyl, hydroxy, acetyloxymethyl,hydroxymethyl or hydrogen.

6) A cyclopentanone derivative of formula [1A] or a pharmacologicallyacceptable salt thereof, according to 5) described above, wherein thecyclopentanone derivative is selected from the group consisting of:

(I) X_(A) is S, Y_(A) is 2-acetylamino-2-carboxyethyl, Z1A and Z3_(A)are hydrogen and, Z2_(A) is carboxy;

(II) X_(A) is S, Y_(A) is 2-acetylamino-2-methoxycarbonylethyl, Z1_(A)and Z3_(A) are hydrogen and, Z2_(A) is carboxy;

(III) X_(A) is S, Y_(A) is 2-acetylamino-2-carboxyethyl, Z1_(A) andZ3_(A) are hydrogen and, Z2_(A) is hydroxy;

(IV) X_(A) is S, Y_(A) is2-acetylamino-3-oxo-3-{1-(2-methoxycarbonyl)pyrrolidinyl}propyl, Z1_(A)and Z3_(A) are hydrogen and, Z2_(A) is hydroxy;

(V) X_(A) is S, Y_(A) is 2-acetylamino-2-methoxycarbonylethyl, Z2_(A)and Z3_(A) are combined together to form an unsubstituted benzene ringand, Z1_(A) is carboxy; and,

(VI) X_(A) is S, Y_(A) is 2-acetylamino-2-carboxyethyl, Z2_(A) andZ3_(A) are combined together to form an unsubstituted benzene ring and,Z1_(A) is carboxy.

7) A 2,3-di-substituted cyclopentanone derivative of formula [1B] or apharmacologically acceptable salt thereof, according to 1) above,wherein:

X_(B) is S, O or SO;

Y_(B) is a straight or branched aliphatic hydrocarbon group having 7 to20 carbon atoms (wherein at least one hydrogen may optionally besubstituted with carboxy or a group derived therefrom or, amino or agroup derived therefrom); and,

Z_(B) is carboxy, COOR3 (wherein R3 is an unsubstituted or substitutedalkyl having 1 to 4 carbon atoms), CH₂OR4 (wherein R4 is hydrogen or anunsubstituted or substituted alkyl having 1 to 4 carbon atoms) or,CH₂OCOR5 (wherein R5 is an unsubstituted or substituted alkyl having 1to 4 carbon atoms).

8) A 2,3-di-substituted cyclopentanone derivative of formula [1B] or apharmacologically acceptable salt thereof, according to 7) describedabove, wherein:

X_(B) is S;

Y_(B) is a straight aliphatic hydrocarbon group having 7 to 20 carbonatoms (wherein at least two hydrogen atoms are substituted with carboxy,COOR6 (wherein R6 is an alkyl, alkenyl or alkynyl having 1 to 4 carbonatoms) or NR7R8 (wherein each of R7 and R8, which may be the same ordifferent and independently represents hydrogen, an alkyl having 1 to 4carbon atoms or an acyl having 1 to 5 carbon atoms); and,

Z_(B) is carboxy, methoxycarbonyl, hydroxymethyl or acetyloxymethyl.

9) A 2,3-di-substituted cyclopentanone derivative of formula [1B] or apharmacologically acceptable salt thereof, according to 8) describedabove, wherein:

X_(B) is S;

Y_(B) is 11-acetylamino-11-carboxy-n-undecyl; and,

Z_(B) is carboxy.

10) A 2,3-di-substituted cyclopentanone derivative of formula [1B] or apharmacologically acceptable salt thereof, according to 1) above,wherein:

X_(B) is S, O or SO;

Y_(B) is a straight or branched aliphatic hydrocarbon group having 1 to6 carbon atoms wherein at least one hydrogen is substituted with COW2{wherein W2 is a saturated heterocyclic ring unsubstituted orsubstituted with carboxy, a hydroxyalkyl having 1 to 4 carbon atoms,phenyl or COOR9 (wherein R9 is an unsubstituted or substituted alkylhaving 1 to 4 carbon atoms)} and, at least one other hydrogen issubstituted with NR10R11 (wherein each of R10 and R11, which may be thesame or different and independently represents hydrogen, anunsubstituted or substituted alkyl having 1 to 4 carbon atoms or, anunsubstituted or substituted acyl having 1 to 5 carbon atoms); and,

Z_(B) is carboxy, COOR3 (wherein R3 is an unsubstituted or substitutedalkyl having 1 to 4 carbon atoms), CH₂OR4 (wherein R4 is hydrogen or anunsubstituted or substituted alkyl having 1 to 4 carbon atoms) or,CH₂OCOR5 (wherein R5 is an unsubstituted or substituted alkyl having 1to 4 carbon atoms).

11) A 2,3-di-substituted cyclopentanone derivative of formula [1B] or apharmacologically acceptable salt thereof, according to 10) describedabove, wherein:

X_(B) is S;

Y_(B) is a straight or branched aliphatic hydrocarbon group having 1 to6 carbon atoms {wherein one hydrogen is substituted with COW3 (whereinW3 is a 1-azetidinyl, 1-piperidyl, 1-pyrrolidinyl, 1-piperazinyl or4-morpholinyl group, which group may be unsubstituted or substitutedwith carboxy, methoxycarbonyl, 2-hydroxyethyl, phenyl ortert-butoxycarbonyl) and one other hydrogen is substituted with NHCOR12(wherein R12 is an alkyl having 1 to 4 carbon atoms)}; and,

Z_(B) is carboxy, methoxycarbonyl, hydroxymethyl or acetyloxy.

12) A 2,3-di-substituted cyclopentanone derivative of formula [1B]described in 1) above or a pharmacologically acceptable salt thereof,according to 11) described above, wherein:

X_(B) is S;

Y_(B) is 2-acetylamino-3-oxo-3-(1-pyrrolidinyl)propyl,2-acetylamino-3-{1-(2-methoxycarbonyl)pyrrolidinyl-3-oxopropyl,2-acetylamino-3-oxo-3-(1-piperidyl)propyl,2-acetylamino-3-(4-morpholinyl)-3-oxopropyl,2-acetylamino-3-{1-(2-methoxycarbonyl)azetidinyl}-3-oxopropyl,2-acetylamino-3-oxo-3-(1-piperazinyl)propyl,2-acetylamino-3-[1-{4-(2-hydroxyethyl)piperazinyl}]-3-oxopropyl,2-acetylamino-3-{1-(4-phenylpiperazinyl)}-3-oxopropyl or2-acetylamino-3-{1-(4-tert-butoxycarbonylpiperazinyl)}-3-oxopropyl; and,

Z_(B) is carboxy or methoxycarbonyl.

13) A 2,3-di-substituted cyclopentanone derivative of formula [1B]described in 1) above or a pharmacologically acceptable salt thereof,according to 1) above, wherein:

X_(B) is S, O or SO;

Y_(B) is a straight or branched aliphatic hydrocarbon group having 1 to6 carbon atoms {wherein at least one hydrogen is substituted with NHCOV1(wherein V1 is an alkyl having 2 to 5 carbon atoms and containing 4 to11 halogen atoms) and, at least one other hydrogen may be furthersubstituted with carboxy or COOR13 (wherein R13 is an unsubstituted orsubstituted alkyl, alkenyl or alkynyl having 1 to 4 carbon atoms)}; and,

Z_(B) is carboxy, COOR3 (wherein R3 is an unsubstituted or substitutedalkyl having 1 to 4 carbon atoms), CH₂OR4 (wherein R4 is hydrogen or anunsubstituted or substituted alkyl having 1 to 4 carbon atoms) orCH₂OCOR5 (wherein R5 is an unsubstituted or substituted alkyl having 1to 4 carbon atoms).

14) A 2,3-di-substituted cyclopentanone derivative of formula [1B]described in 1) above or a pharmacologically acceptable salt thereof,according to 13) described above, wherein:

X_(B) is S;

Y_(B) is a straight aliphatic hydrocarbon group having 1 to 6 carbonatoms {wherein one hydrogen is substituted with NHCOV2 (wherein V2 is analkyl having 2 to 5 carbon atoms and containing 4 to 11 fluorine atoms)and, one other hydrogen is further substituted with carboxy or COOR13′(wherein R13′ is an alkyl, alkenyl or alkynyl having 1 to 4 carbonatoms)}; and,

Z_(B) is carboxy, methoxycarbonyl, hydroxymethyl or acetyloxymethyl.

15) A 2,3-di-substituted cyclopentanone derivative of formula [1B]described in 1) above or a pharmacologically acceptable salt thereof,according to 14) described above, wherein:

X_(B) is S;

Y_(B) is 2-carboxy-2-(pentafluoropropionyl)aminoethyl; and,

Z_(B) is carboxy or hydroxymethyl.

16) A 2,3-di-substituted cyclopentanone derivative of formula [1B]described in 1) above or a pharmacologically acceptable salt thereof,according to 1) above, wherein:

X_(B) is S, O or SO;

Y_(B) is a straight or branched aliphatic hydrocarbon group having 1 to6 carbon atoms {wherein at least one hydrogen is substituted with asubstituted or unsubstituted monocyclic aromatic heterocyclic ring andat least one other hydrogen is further substituted with NR15R16 (whereineach of R15 and R16, which may be the same or different andindependently represents hydrogen, an unsubstituted or substituted alkylhaving 1 to 4 carbon atoms, or an unsubstituted or substituted acylhaving 1 to 5 carbon atoms)}; and,

Z_(B) is carboxy, COOR3 (wherein R3 is an unsubstituted or substitutedalkyl having 1 to 4 carbon atoms), CH₂OR4 (wherein R4 is hydrogen or anunsubstituted or substituted alkyl having 1 to 4 carbon atoms) orCH₂OCOR5 (wherein R5 is an unsubstituted or substituted alkyl having 1to 4 carbon atoms).

17) A 2,3-di-substituted cyclopentanone derivative of formula [1B]described in 1) above or a pharmacologically acceptable salt thereof,according to 16) described above, wherein:

X_(B) is S;

Y_(B) is a straight aliphatic hydrocarbon group having 1 to 4 carbonatoms {wherein one hydrogen should be substituted with a pyridine ringunsubstituted or substituted with an alkyl having 1 to 4 carbon atoms orwith 5-tetrazolyl, and one other hydrogen may be further substitutedwith NHCOR17 (wherein R17 is an alkyl having 1 to 4 carbon atoms}; and,

Z_(B) is carboxy, methoxycarbonyl, hydroxymethyl or acetyloxymethyl.

18) A 2,3-di-substituted cyclopentanone derivative of formula [1B]described in 1) above or a pharmacologically acceptable salt thereof,according to 17) described above, wherein:

X_(B) is S;

Y_(B) is 3-(3-pyridyl)propyl, 3-{3-(1-methylpyridinium iodide)}propyl or2-acetylamino-2-(5-tetrazolyl)ethyl;

Z_(B) is carboxy or methoxycarbonyl.

19) A cyclopentenone derivative of formula [1C] described in 1) above ora pharmacologically acceptable salt thereof, according to 1) above,wherein:

ring A forms an oxo-conjugated double bond together with the carbon atombound to CH2-Xc-Yc;

X_(c) is S, O or SO;

Y_(c) is an aliphatic hydrocarbon group having 1 to 6 carbon atoms(wherein at least one hydrogen is substituted with carboxy or a groupderived therefrom, amino or a group derived therefrom or, hydroxy or agroup derived therefrom); and,

each of Z1_(c), Z2_(c) and Z3_(c), which may be the same or differentand independently represents carboxy or a group derived therefrom,hydroxy or a group derived therefrom, amino or a group derivedtherefrom, a substituted or unsubstituted alkyl or alkenyl having 1 to 4carbon atoms, a monocyclic aromatic heterocyclic ring, a halogen orhydrogen.

20) A cyclopentenone derivative of formula [iC] described in 1) above ora pharmacologically acceptable salt thereof, according to 19) describedabove, wherein:

ring A forms an oxo-conjugated double bond together with the carbon atombound to CH₂—X_(c)—Y_(c);

X_(c) is S, O or SO;

Y_(c) is an aliphatic hydrocarbon group having 1 to 6 carbon atoms(wherein at least one hydrogen is substituted with carboxy, COOR1(wherein R1 is a substituted or unsubstituted alkyl or alkenyl having 1to 4 carbon atoms), CONR2R3 (wherein each of R2 and R3 which may be thesame or different and independently represents hydrogen or anunsubstituted or substituted alkyl having 1 to 4 carbon atoms), COW(wherein W is a heterocyclic ring unsubstituted or substituted withcarboxy or a group derived therefrom or, amino or a group derivedtherefrom), NR4R5 (wherein each of R4 and R5, which may be the same ordifferent and independently represents hydrogen, an unsubstituted orsubstituted alkyl having 1 to 4 carbon atoms or, an unsubstituted orsubstituted acyl having 1 to 5 carbon atoms) or OR6 (wherein R6 ishydrogen, an unsubstituted or substituted alkyl having 1 to 4 carbonatoms or, an unsubstituted or substituted acyl having 1 to 5 carbonatoms); and,

each of Z1_(c), Z2_(c) and Z3_(c) independently represents carboxy,COOR7 (wherein R7 is an unsubstituted or substituted alkyl having 1 to 4carbon atoms), CONR8R9 (wherein each of R8 and R9, which may be the sameor different and independently represents hydrogen or an unsubstitutedor substituted alkyl having 1 to 4 carbon atoms), cyano, CH₂OR10(wherein R10 is hydrogen, an unsubstituted or substituted alkyl having 1to 4 carbon atoms or, an unsubstituted or substituted acyl having 1 to 5carbon atoms), hydroxy, OCOR11 (wherein R11 is an unsubstituted orsubstituted alkyl having 1 to 4 carbon atoms), NR12R13 (wherein each ofR12 and R13, which may be the same or different and independentlyrepresents hydrogen, an unsubstituted or substituted alkyl having 1 to 4carbon atoms or, an unsubstituted or substituted acyl having 1 to 5carbon atoms), 5-tetrazolyl, chlorine, fluorine or hydrogen.

21) A cyclopentenone derivative of formula [1C] described in 1) above ora pharmacologically acceptable salt thereof, according to 20) describedabove, wherein:

ring A forms an oxo-conjugated double bond together with the carbon atombound to CH₂—X_(c)—Y_(c);

X_(c) is S;

Y_(c) is an aliphatic hydrocarbon group having 1 to 6 carbon atoms(wherein at least two hydrogen atoms are substituted with carboxy,COOR1′ (wherein R1′ is an alkyl or alkenyl having 1 to 4 carbon atoms),NHCOR14 (wherein R14 is an alkyl having 1 to 4 carbon atoms whichhydrogen may optionally be substituted with fluorine), hydroxy, orOCOR15 (wherein R15 is an alkyl having 1 to 4 carbon atoms); and,

each of Z1_(c), Z2_(c) and Z3_(c) is carboxy, COOR7′ (wherein R7′ is analkyl having 1 to 4 carbon atoms) or CH₂OR10′ (wherein R10′ is hydrogenor an acyl having 1 to 5 carbon atoms).

22) A cyclopentenone derivative of formula [1C] described in 1) above ora pharmacologically acceptable salt thereof, according to 21) describedabove, wherein:

ring A forms an oxo-conjugated double bond together with the carbon atombound to CH₂—X_(c)—Y_(c);

X_(c) is S;

Y_(c) is 2-acetylamino-2-carboxyethyl; and,

either Z1_(c) or Z2_(c) is hydroxy and the remaining groups out ofZ1_(c), Z2_(c) and Z3₃ are all hydrogen.

23) A cyclopentenone derivative of formula [1C] described in 1) above ora pharmacologically acceptable salt thereof, according to 1) above,wherein:

ring A forms an oxo-conjugated double bond without containing the carbonatom bound to CH₂—X_(c)—Y_(c);

X_(c) is S, O or SO;

Y_(c) is an aliphatic hydrocarbon group having 1 to 6 carbon atoms(wherein at least one hydrogen is substituted with carboxy or a groupderived therefrom, amino or a group derived therefrom or, hydroxy or agroup derived therefrom); and,

each of Z1_(c), Z2_(c) and Z3_(c) is carboxy or a group derivedtherefrom, an unsubstituted or substituted alkyl or alkenyl having 1 to4 carbon atoms, hydroxy or a group derived therefrom, amino or a groupderived therefrom, a monocyclic aromatic heterocyclic ring, a halogen orhydrogen.

24) A cyclopentenone derivative of formula [1C] described in 1) above ora pharmacologically acceptable salt thereof, according to 23) describedabove, wherein:

ring A forms an oxo-conjugated double bond without containing the carbonatom bound to CH₂—X_(c)—Y_(c);

X_(c) is S, O or SO;

Y_(c) is an aliphatic hydrocarbon group having 1 to 6 carbon atoms(wherein at least one hydrogen is substituted with carboxy, COOR1(wherein R1 is a substituted or unsubstituted alkyl or alkenyl having 1to 4 carbon atoms), CONR2R3 (wherein each of R2 and R3 which may be thesame or different and independently represents hydrogen or anunsubstituted or substituted alkyl having 1 to 4 carbon atoms), COW(wherein W is a heterocyclic ring unsubstituted or substituted withcarboxy or a group derived therefrom or, amino or a group derivedtherefrom), NR4R5 (wherein each of R4 and R5, which may be the same ordifferent and independently represents hydrogen, an unsubstituted orsubstituted alkyl having 1 to 4 carbon atoms or, an unsubstituted orsubstituted acyl having 1 to 5 carbon atoms) or OR6 (wherein R6 ishydrogen, an unsubstituted or substituted alkyl having 1 to 4 carbonatoms or, an unsubstituted or substituted acyl having 1 to 5 carbonatoms); and,

each of Z1_(c), Z2_(c) and Z3_(c) independently represents carboxy,COOR7 (wherein R7 is an unsubstituted or substituted alkyl having 1 to 4carbon atoms), CONR8R9 (wherein each of R8 and R9, which may be the sameor different and independently represents hydrogen or an unsubstitutedor substituted alkyl having 1 to 4 carbon atoms), cyano, CH₂OR10(wherein R10 is hydrogen, an unsubstituted or substituted alkyl having 1to 4 carbon atoms or, an unsubstituted or substituted acyl having 1 to 5carbon atoms), hydroxy, OCOR11 (wherein R11 is an unsubstituted orsubstituted alkyl having 1 to 4 carbon atoms), NR12R13 (wherein each ofR12 and R13, which may be the same or different and independentlyrepresents hydrogen, an unsubstituted or substituted alkyl having 1 to 4carbon atoms or, an unsubstituted or substituted acyl having 1 to 5carbon atoms), 5-tetrazolyl, chlorine, fluorine or hydrogen.

25) A cyclopentenone derivative of formula [1C] described in 1) above ora pharmacologically acceptable salt thereof, according to 24) describedabove, wherein:

ring A forms an oxo-conjugated double bond without containing the carbonatom bound to CH₂—X_(c)—Y_(c);

X_(c) is S;

Y_(c) is an aliphatic hydrocarbon group having 1 to 6 carbon atoms(wherein at least two hydrogen atoms are substituted with carboxy,COOR1′ (wherein R1′ is an alkyl or alkenyl having 1 to 4 carbon atoms),NHCOR14 (wherein R14 is an alkyl having 1 to 4 carbon atoms whichhydrogen may optionally be substituted with fluorine), hydroxy or OCOR15(wherein R15 is an alkyl having 1 to 4 carbon atoms); and,

each of Z1_(c), Z2_(c) and Z3₃ is carboxy, COOR7′ (wherein R7′ is analkyl having 1 to 4 carbon atoms) or CH₂OR10′ (wherein R10′ is hydrogenor an acyl having 1 to 5 carbon atoms).

26) A cyclopentenone derivative of formula [1C] described in 1) above ora pharmacologically acceptable salt thereof, according to 25) describedabove, wherein:

ring A forms an oxo-conjugated double bond without containing the carbonatom bound to CH₂—X_(c)—Y_(c);

X_(c) is S;

Y_(c) is 2-acetylamino-2-carboxyethyl; and,

all of Z1_(c), Z2_(c) and Z3_(c) are hydrogen.

27) A ketone derivative of formula [1D] described in 1) above or apharmacologically acceptable salt thereof, according to 1) above,wherein:

A_(D) is an unsubstituted or substituted aliphatic hydrocarbon grouphaving 1 to 4 carbon atoms;

B_(D) is hydrogen or an unsubstituted or substituted aliphatichydrocarbon group having 1 to 4 carbon atoms;

X_(D) is S, O, or SO;

Y_(D) is an aliphatic hydrocarbon group having 1 to 6 carbon atoms(wherein at least one hydrogen is substituted with carboxy or a groupderived therefrom, amino or a group derived therefrom or, hydroxy or agroup derived therefrom); and,

Z_(D) is carboxy or a group derived therefrom, an unsubstituted orsubstituted alkyl or alkenyl having 1 to 4 carbon atoms, hydroxy or agroup derived therefrom, amino or a group derived therefrom, amonocyclic aromatic heterocyclic ring, a halogen or hydrogen.

28) A ketone derivative of formula [1D] described in 1) above or apharmacologically acceptable salt thereof, according to 27) describedabove, wherein:

A_(D) is an aliphatic hydrocarbon group having 1 to 4 carbon atoms;

B_(D) is hydrogen or an aliphatic hydrocarbon group having 1 to 4 carbonatoms;

X_(D) is S, O, or SO;

Y_(D) is an aliphatic hydrocarbon group having 1 to 6 carbon atoms(wherein at least one hydrogen is substituted with carboxy, COOR1(wherein R1 is a substituted or unsubstituted alkyl or alkenyl having 1to 4 carbon atoms), CONR2R3 (wherein each of R2 and R3 which may be thesame or different and independently represents hydrogen or anunsubstituted or substituted alkyl having 1 to 4 carbon atoms), COW(wherein W is a heterocyclic ring unsubstituted or substituted withcarboxy or a group derived therefrom or, amino or a group derivedtherefrom), NR4R5 (wherein each of R4 and R5, which may be the same ordifferent and independently represents hydrogen, an unsubstituted orsubstituted alkyl having 1 to 4 carbon atoms or, an unsubstituted orsubstituted acyl having 1 to 5 carbon atoms) or OR6 (wherein R6 ishydrogen, an unsubstituted or substituted alkyl having 1 to 4 carbonatoms or, an unsubstituted or substituted acyl having 1 to 5 carbonatoms); and,

Z_(D) is carboxy, COOR7 (wherein R7 is an unsubstituted or substitutedalkyl having 1 to 4 carbon atoms), CONR8R9 (wherein each of R8 and R9,which may be the same or different and independently represents hydrogenor an unsubstituted or substituted alkyl having 1 to 4 carbon atoms),cyano, CH₂OR10 (wherein R10 is hydrogen, an unsubstituted or substitutedalkyl having 1 to 4 carbon atoms or, an unsubstituted or substitutedacyl having 1 to 5 carbon atoms), hydroxy, OCOR11 (wherein R11 is anunsubstituted or substituted alkyl having 1 to 4 carbon atoms), NR12R13(wherein each of R12 and R13 which may be the same or different andindependently represents hydrogen, an unsubstituted or substituted alkylhaving 1 to 4 carbon atoms or, an unsubstituted or substituted acylhaving 1 to 5 carbon atoms), 5-tetrazolyl, chlorine, fluorine orhydrogen.

29) A ketone derivative of formula [1D] described in 1) above or apharmacologically acceptable salt thereof, according to 28) describedabove, wherein:

A_(D) is an alkyl having 1 to 4 carbon atoms;

B_(D) is hydrogen or an alkyl having 1 to 4 carbon atoms;

X_(D) is S;

Y_(D) is an aliphatic hydrocarbon group having 1 to 6 carbon atoms(wherein at least two hydrogen atoms are substituted with carboxy,COOR1′ (wherein R1 is an alkyl or alkenyl having 1 to 4 carbon atoms),NHCOR14 (wherein R14 is an alkyl having 1 to 4 carbon atoms whichhydrogen may optionally be substituted with fluorine), hydroxy or OCOR15(wherein R15 is an alkyl having 1 to 4 carbon atoms);

Z_(D) is carboxy, COOR7′ (wherein R7′ is an alkyl having 1 to 4 carbonatoms) or CH₂OR10′ (wherein R10′ is hydrogen or an acyl having 1 to 5carbon atoms).

30) A ketone derivative of formula [1D] described in 1) above or apharmacologically acceptable salt thereof, according to 29) describedabove, wherein:

A_(D) is methyl;

B_(D) is hydrogen;

X_(D) is S;

Y_(D) is 2-acetylamino-2-carboxyethyl or2-acetylamino-2-methoxycarbonylethyl; and,

Z_(D) is carboxy, methoxycarbonyl, acetoxymethyl or hydroxymethyl.

31) A ketone derivative of formula [1D] described in 1) above or apharmacologically acceptable salt thereof, according to 1) above,wherein:

A_(D) is an unsubstituted or substituted aromatic hydrocarbon, aromaticheterocyclic ring or saturated heterocyclic ring;

B_(D) is hydrogen or an unsubstituted or substituted aliphatichydrocarbon group having 1 to 4 carbon atoms;

X_(D) is S, O, or SO;

Y_(D) is an aliphatic hydrocarbon group having 1 to 6 carbon atoms(wherein at least one hydrogen is substituted with carboxy or a groupderived therefrom, amino or a group derived therefrom or, hydroxy or agroup derived therefrom); and,

Z_(D) is carboxy or a group derived therefrom, an unsubstituted orsubstituted alkyl or alkenyl having 1 to 4 carbon atoms, hydroxy or agroup derived therefrom, amino or a group derived therefrom, amonocyclic aromatic heterocyclic ring, a halogen or hydrogen.

32) A ketone derivative of formula [1D] described in 1) above or apharmacologically acceptable salt thereof, according to 31) describedabove, wherein:

A_(D) is an unsubstituted benzene ring wherein, when substituted, 1 to 3hydrogen atoms are substituted with an unsubstituted or substitutedalkyl group having 1 to 4 carbon atoms, a halogen, hydroxy, an alkoxyhaving 1 to 4 carbon atoms, amino, an alkyl- or dialkylamino having 1 to4 carbon atoms, thiol, carboxy, an alkoxycarbonyl having 1 to 4 carbonatoms, an acyloxy having 1 to 5 carbon atoms, an acylthio having 1 to 5carbon atoms, an acylamino having 1 to 5 carbon atoms, cyano ortrifluoromethyl;

B_(D) is hydrogen or an aliphatic hydrocarbon group having 1 to 4 carbonatoms;

X_(D) is S, O, or SO;

Y_(D) is an aliphatic hydrocarbon group having 1 to 6 carbon atoms(wherein at least one hydrogen is substituted with carboxy, COOR1(wherein R1 is a substituted or unsubstituted alkyl or alkenyl having 1to 4 carbon atoms), CONR2R3 (wherein each of R2 and R3 which may be thesame or different and independently represents hydrogen or anunsubstituted or substituted alkyl having 1 to 4 carbon atoms), COW(wherein W is a heterocyclic ring which may be unsubstituted orsubstituted with carboxy or a group derived therefrom or, amino or agroup derived therefrom), NR4R5 (wherein each of R4 and R5, which may bethe same or different and independently represents hydrogen, anunsubstituted or substituted alkyl having 1 to 4 carbon atoms or, anunsubstituted or substituted acyl having 1 to 5 carbon atoms) or OR6(wherein R6 is hydrogen, an unsubstituted or substituted alkyl having 1to 4 carbon atoms or, an unsubstituted or substituted acyl having 1 to 5carbon atoms); and,

Z_(D) is carboxy, COOR7 (wherein R7 is an unsubstituted or substitutedalkyl having 1 to 4 carbon atoms), CONR8R9 (wherein each of R8 and R9,which may be the same or different and independently represents hydrogenor an unsubstituted or substituted alkyl having 1 to 4 carbon atoms),cyano, CH₂OR10 (wherein R10 is hydrogen, an unsubstituted or substitutedalkyl having 1 to 4 carbon atoms or, an unsubstituted or substitutedacyl having 1 to 5 carbon atoms), hydroxy, OCOR11 (wherein R11 is anunsubstituted or substituted alkyl having 1 to 4 carbon atoms), NR12R13(wherein each of R12 and R13 which may be the same or different andindependently represents hydrogen, an unsubstituted or substituted alkylhaving 1 to 4 carbon atoms or, an unsubstituted or substituted acylhaving 1 to 5 carbon atoms), 5-tetrazolyl, chlorine, fluorine orhydrogen.

33) A ketone derivative of formula [1D] described in 1) above or apharmacologically acceptable salt thereof, according to 32) describedabove, wherein:

A_(D) is an unsubstituted or substituted benzene ring, wherein, whensubstituted, 1 to 3 hydrogen atoms are substituted with methyl, methoxy,methoxycarbonyl, nitro, cyano, a halogen or trifluoromethyl;

B_(D) is hydrogen or an alkyl having 1 to 4 carbon atoms;

X_(D) is S;

Y_(D) is an aliphatic hydrocarbon group having 1 to 6 carbon atoms(wherein at least two hydrogen atoms are substituted with carboxy,COOR1′ (wherein R1′ is an alkyl or alkenyl having 1 to 4 carbon atoms),NHCOR14 (wherein R14 is an alkyl having 1 to 4 carbon atoms whichhydrogen may optionally be substituted with fluorine), hydroxy or OCOR15(wherein R15 is an alkyl having 1 to 4 carbon atoms);

Z_(D) is carboxy, COOR7′ (wherein R7′ is an alkyl having 1 to 4 carbonatoms) or CH₂OR10′ (wherein R10′ is hydrogen or an acyl having 1 to 5carbon atoms).

34) A ketone derivative of formula [1D] described in 1) above or apharmacologically acceptable salt thereof, according to 33) describedabove, wherein:

A_(D) is an unsubstituted benzene ring or a benzene ring substitutedwith methyl or methoxy;

B_(D) is hydrogen;

X_(D) is S;

Y_(D) is 2-acetylamino-2-carboxyethyl,2-acetylamino-2-methoxycarbonylethyl or 2-acetylaminoethyl; and,

Z_(D) is carboxy, methoxycarbonyl, acetoxymethyl or hydroxymethyl.

35) A ketone derivative of formula [1D] described in 1) above or apharmacologically acceptable salt thereof, according to 1) above,wherein:

A_(D) and B_(D) are combined together to form an unsubstituted orsubstituted cycloalkan-1-one ring having 3 to 7 carbon atoms (except for5 carbon atoms);

X_(D) is S, O, or SO;

Y_(D) is an aliphatic hydrocarbon group having 1 to 6 carbon atoms(wherein at least one hydrogen is substituted with carboxy or a groupderived therefrom, amino or a group derived therefrom or, hydroxy or agroup derived therefrom); and,

Z_(D) is carboxy or a group derived therefrom, an unsubstituted orsubstituted alkyl or alkenyl having 1 to 4 carbon atoms, hydroxy or agroup derived therefrom, amino or a group derived therefrom, amonocyclic aromatic heterocyclic ring, a halogen or hydrogen.

36) A ketone derivative of formula [1D] described in 1) above or apharmacologically acceptable salt thereof, according to 35) describedabove, wherein:

A_(D) and B_(D) are combined together to form an unsubstituted orsubstituted cyclobutan-1-one ring or cyclohexan-1-one ring;

X_(D) is S, O, or SO;

Y_(D) is an aliphatic hydrocarbon group having 1 to 6 carbon atoms(wherein at least one hydrogen is substituted with carboxy, COOR1(wherein R1 is a substituted or unsubstituted alkyl or alkenyl having 1to 4 carbon atoms), CONR2R3 (wherein each of R2 and R3 which may be thesame or different and independently represents hydrogen or anunsubstituted or substituted alkyl having 1 to 4 carbon atoms), COW(wherein W is a heterocyclic ring which may be unsubstituted orsubstituted with carboxy or a group derived therefrom or, amino or agroup derived therefrom), NR4R5 (wherein each of R4 and R5, which may bethe same or different and independently represents hydrogen, anunsubstituted or substituted alkyl having 1 to 4 carbon atoms or, anunsubstituted or substituted acyl having 1 to 5 carbon atoms) or OR6(wherein R6 is hydrogen, an unsubstituted or substituted alkyl having 1to 4 carbon atoms or, an unsubstituted or substituted acyl having 1 to 5carbon atoms); and,

Z_(D) is carboxy, COOR7 (wherein R7 is an unsubstituted or substitutedalkyl having 1 to 4 carbon atoms), CONR8R9 (wherein each of R8 and R9,which may be the same or different and independently represents hydrogenor an unsubstituted or substituted alkyl having 1 to 4 carbon atoms),cyano, CH₂OR10 (wherein R10 is hydrogen, an unsubstituted or substitutedalkyl having 1 to 4 carbon atoms or, an unsubstituted or substitutedacyl having 1 to 5 carbon atoms), hydroxy, OCOR11 (wherein R11 is anunsubstituted or substituted alkyl having 1 to 4 carbon atoms), NR12R13(wherein each of R12 and R13, which may be the same or different andindependently represents hydrogen, an unsubstituted or substituted alkylhaving 1 to 4 carbon atoms or, an unsubstituted or substituted acylhaving 1 to 5 carbon atoms), 5-tetrazolyl, chlorine, fluorine orhydrogen.

37) A ketone derivative of formula [1D] described in 1) above or apharmacologically acceptable salt thereof, according to 36) describedabove, wherein:

A_(D) and B_(D) are combined together to form a cyclobutan-1-one ring orcyclohexan-1-one ring;

X_(D) is S;

Y_(D) is an aliphatic hydrocarbon group having 1 to 6 carbon atoms(wherein at least two hydrogen atoms are substituted with carboxy,COOR1′ (wherein R1′ is an alkyl or alkenyl having 1 to 4 carbon atoms),NHCOR14 (wherein R14 is an alkyl having 1 to 4 carbon atoms whichhydrogen may optionally be substituted with fluorine), hydroxy or OCOR15(wherein R15 is an alkyl having 1 to 4 carbon atoms);

Z_(D) is carboxy, COOR7′ (wherein R7′ is an alkyl having 1 to 4 carbonatoms) or CH₂OR10′ (wherein R10′ is hydrogen or an acyl having 1 to 5carbon atoms).

38) A ketone derivative of formula [1D] described in 1) above or apharmacologically acceptable salt thereof, according to 37), wherein:

(I) A_(D) and B_(D) are combined together to form a cyclobutan-1-onering, X_(D) is S, Y_(D) is 2-acetylamino-2-carboxyethyl and, Z_(D) iscarboxy;

(II) A_(D) and B_(D) are combined together to form a cyclobutan-1-onering, X_(D) is S, Y_(D) is 2-acetylamino-2-methoxycarbonylethyl and,Z_(D) is methoxycarbonyl;

(III) A_(D) and B_(D) are combined together to form a cyclobutan-1-onering, X_(D) is S, Y_(D) is 2,3-dihydroxy-n-propyl and, Z_(D) isacetoxymethyl; and,

(IV) A_(D) and B_(D) are combined together to form a cyclohexan-1-onering, X_(D) is S, Y_(D) is 2-acetylamino-2-carboxyethyl and, Z_(D) iscarboxy.

39) A β-di-substituted aminoketone derivative of formula [1F] describedin 1) above or a pharmacologically acceptable salt thereof, accordingto 1) above, wherein:

A_(F) is an unsubstituted or substituted aliphatic hydrocarbon grouphaving 1 to 4 carbon atoms;

B_(F) is hydrogen or, an unsubstituted or substituted aliphatichydrocarbon group having 1 to 4 carbon atoms;

X_(F) and Y_(F) are a straight or branched aliphatic hydrocarbon grouphaving 1 to 10 carbon atoms (wherein at least one hydrogen mayoptionally be substituted with carboxy or a group derived therefrom,amino or a group derived therefrom or, hydroxy or a group derivedtherefrom) or; X_(F) and Y_(F) are bound to each other directly or via ahetero atom to form a monocyclic heterocyclic ring (wherein at least onehydrogen may optionally be substituted with an alkyl having 1 to 4carbon atoms, phenyl, carboxy or a group derived therefrom, amino or agroup derived therefrom or, hydroxy or a group derived therefrom);

Z_(F) is carboxy or a group derived therefrom, an unsubstituted orsubstituted alkyl or alkenyl having 1 to 4 carbon atoms, hydroxy or agroup derived therefrom, amino or a group derived therefrom, amonocyclic aromatic heterocyclic ring or a halogen.

40) A β-di-substituted aminoketone derivative of formula [1F] describedin 1) above or a pharmacologically acceptable salt thereof, according to39) described above, wherein:

A_(F) is methyl, ethyl, n-propyl or isopropyl, which may beunsubstituted or substituted;

B_(F) is hydrogen;

each of X_(F) and Y_(F), which may be the same or different andindependently represents an alkyl having 1 to 6 carbon atoms or, X_(F)and Y_(F) are bound to each other directly or via a hetero atom to forma monocyclic heteroaryl ring which may be unsubstituted or substitutedwith an alkyl having 1 to 4 carbon atoms or phenyl;

Z_(F) is carboxy, COOR1 (wherein R1 is a substituted or unsubstitutedalkyl having 1 to 4 carbon atoms or, phenyl), CONR2R3 (wherein each ofR2 and R3, which may be the same or different and independentlyrepresents hydrogen or an unsubstituted or substituted alkyl having 1 to4 carbon atoms), cyano, CH₂OR4 (wherein R4 is hydrogen, an unsubstitutedor substituted alkyl having 1 to 4 carbon atoms or, an unsubstituted orsubstituted acyl having 1 to 5 carbon atoms), hydroxy, OR5 (wherein R5is an unsubstituted or substituted alkyl having 1 to 4 carbon atoms or,an unsubstituted or substituted acyl having 1 to 5 carbon atoms), NR6R7(wherein each of R6 and R7, which may be the same or different andindependently represents hydrogen, an unsubstituted or substituted alkylhaving 1 to 4 carbon atoms or, an unsubstituted or substituted acylhaving 1 to 5 carbon atoms), 5-tetrazolyl, chlorine or fluorine. 41) Aβ-di-substituted aminoketone derivative of formula [1F] described in 1)above or a pharmacologically acceptable salt thereof, according to 40)described above, wherein:

A_(F) is methyl;

B_(F) is hydrogen;

X_(F) and Y_(F) are both ethyl n-propyl or isopropyl, X_(F) and Y_(F)are bound to each other directly or via a hetero atom to form apyrrolidine, piperidine, morpholine, 4-methylpiperazine or4-phenylpiperazine ring;

Z_(F) is carboxy, COOR1′ (wherein R1′ is an alkyl having 1 to 4 carbonatoms), CONR2′R3′ (wherein R2′ and R3′, which may be the same ordifferent and each is hydrogen or an alkyl having 1 to 4 carbon atoms)or cyano.

42) A β-di-substituted aminoketone derivative of formula [1F] describedin 1) above or a pharmacologically acceptable salt thereof, accordingto 1) above, wherein:

A_(F) is an unsubstituted or substituted aryl, heteroaryl or saturatedheterocyclic ring;

B_(F) is hydrogen or, an unsubstituted or substituted aliphatichydrocarbon group having 1 to 4 carbon atoms;

X_(F) and Y_(F) are a straight or branched aliphatic hydrocarbon grouphaving 1 to 10 carbon atoms (wherein at least one hydrogen mayoptionally be substituted with carboxy or a group derived therefrom,amino or a group derived therefrom or, hydroxy or a group derivedtherefrom) or, X_(F) and Y_(F) are bound to each other directly or via ahetero atom to form a heterocyclic ring (wherein at least one hydrogenmay optionally be substituted with an alkyl having 1 to 4 carbon atoms,phenyl, carboxy or a group derived therefrom, amino or a group derivedtherefrom or, hydroxy or a group derived therefrom);

Z_(F) is carboxy or a group derived therefrom, an unsubstituted orsubstituted alkyl or alkenyl having 1 to 4 carbon atoms, hydroxy or agroup derived therefrom, amino or a group derived therefrom, amonocyclic aromatic heterocyclic ring or a halogen.

43) A β-di-substituted aminoketone derivative of formula [1F] describedin 1) above or a pharmacologically acceptable salt thereof, according to42) described above, wherein:

A_(F) is an unsubstituted or substituted benzene ring or, monocyclicaromatic heterocyclic ring;

B_(F) is hydrogen;

X_(F) and Y_(F), which may be the same or different, are a straight orbranched aliphatic hydrocarbon group having 1 to 6 or, X_(F) and Y_(F)are bound to each other directly or via a hetero atom to form aheterocyclic ring unsubstituted or substituted with an alkyl having 1 to4 carbon atoms or phenyl;

Z_(F) is carboxy, COOR1 (wherein R1 is a substituted or unsubstitutedalkyl having 1 to 4 carbon atoms or, phenyl), CONR2R3 (wherein each ofR2 and R3, which may be the same or different and independentlyrepresents hydrogen or an unsubstituted or substituted alkyl having 1 to4 carbon atoms), cyano, CH₂OR4 (wherein R4 is hydrogen, an unsubstitutedor substituted alkyl having 1 to 4 carbon atoms or, an unsubstituted orsubstituted acyl having 1 to 5 carbon atoms), hydroxy, OR5 (wherein R5is an unsubstituted or substituted alkyl having 1 to 4 carbon atoms or,an unsubstituted or substituted acyl having 1 to 5 carbon atoms), NR6R7(wherein each of R6 and R7, which may be the same or different andindependently represents hydrogen, an unsubstituted or substituted alkylhaving 1 to 4 carbon atoms or, an unsubstituted or substituted acylhaving 1 to 5 carbon atoms), 5-tetrazolyl, chlorine or fluorine.

44) A β-di-substituted aminoketone derivative of formula [1F] describedin 1) above or a pharmacologically acceptable salt thereof, according to43) described above, wherein:

A_(F) is an unsubstituted or substituted benzene ring wherein, whensubstituted, 1 to 3 hydrogen atoms are substituted with an alkyl having1 to 4 carbon atoms, a halogen, hydroxy, an alkoxy having 1 to 4 carbonatoms, amino, an alkyl- or dialkylamino having 1 to 4 carbon atoms,thiol, carboxy, an alkoxycarbonyl having 1 to 4 carbon atoms, an acyloxyhaving 1 to 5 carbon atoms, an acylthio having 1 to 5 carbon atoms, anacylamino having 1 to 5 carbon atoms, cyano or trifluoromethyl;

B_(F) is hydrogen;

each of X_(F) and Y_(F), which may be the same or different andindependently represents an alkyl having 1 to 6 carbon atoms or, X_(F)and Y_(F) are bound to each other directly or via a hetero atom to forma monocyclic heterocyclic ring unsubstituted or substituted with analkyl having 1 to 4 carbon atoms or phenyl;

Z_(F) is carboxy, COOR1′ (wherein R1′ is an alkyl having 1 to 4 carbonatoms), CONR2′R3′ (wherein R2′ and R3′ , which may be the same ordifferent and each is hydrogen or an alkyl having 1 to 4 carbon atoms),cyano, or CH₂OR4′ (wherein R4′ is hydrogen, an alkyl having 1 to 4carbon atoms or an acyl having 1 to 5 carbon atoms).

45) A β-di-substituted aminoketone derivative of formula [1F] describedin 1) above or a pharmacologically acceptable salt thereof, according to44) described above, wherein:

A_(F) is an unsubstituted or substituted benzene ring, wherein, whensubstituted, 1 to 3 hydrogen atoms are substituted with methyl, methoxy,methoxycarbonyl, nitro, cyano, a halogen or trifluoromethyl;

B_(F) is hydrogen;

X_(F) and Y_(F) are both ethyl, n-propyl or isopropyl; or, X_(F) andY_(F) are bound to each other directly or via a hetero atom to form apyrrolidine, piperidine, morpholine, 4-methylpiperazine or4-phenylpiperazine ring;

Z_(F) is carboxy, COOR1″ (wherein R1″ is methyl or ethyl), CONR2″R3″(wherein R2″ and R3″, which may be the same or different and each ishydrogen, methyl or ethyl) or cyano.

46) A β-di-substituted aminoketone derivative of formula [1F] describedin 1) above or a pharmacologically acceptable salt thereof, accordingto 1) above, wherein:

A_(F) and B_(F) are combined together to form an unsubstituted orsubstituted cycloalkan-1-one ring having 3 to 7 carbon atoms or, A_(F)and B_(F) are combined together to form a cycloalkan-1-one ring having 3to 7 carbon atoms, which ring is fused with an aromatic hydrocarbon or aaromatic heterocyclic ring.

X_(F) and Y_(F) are a straight or branched aliphatic hydrocarbon grouphaving 1 to 10 carbon atoms (wherein at least one hydrogen mayoptionally be substituted with carboxy or a group derived therefrom,amino or a group derived therefrom or, hydroxy or a group derivedtherefrom) or, X_(F) and Y_(F) are bound to each other directly or via ahetero atom to form a heterocyclic ring (wherein at least one hydrogenmay optionally be substituted with an alkyl having 1 to 4 carbon atoms,phenyl, carboxy or a group derived therefrom, amino or a group derivedtherefrom or, hydroxy or a group derived therefrom);

Z_(F) is carboxy or a group derived therefrom, an unsubstituted orsubstituted alkyl or alkenyl having 1 to 4 carbon atoms, hydroxy or agroup derived therefrom, amino or a group derived therefrom, amonocyclic aromatic heterocyclic ring or a halogen.

47) A β-di-substituted aminoketone derivative of formula [1F] describedin 1) above or a pharmacologically acceptable salt thereof, according to46) described above, wherein:

A_(F) and B_(F) are combined together to form an unsubstituted orsubstituted cycloalkan-1-one ring having 4 to 6 carbon atoms or, to forman unsubstituted or substituted cycloalkan-1-one ring having 4 to 6carbon atoms which is fused with an aromatic hydrocarbon or monocyclicaromatic heterocyclic ring;

each of X_(F) and Y_(F), which may be the same or different andindependently is a straight or branched aliphatic hydrocarbon grouphaving 1 to 6 carbon atoms or, X_(F) and Y_(F) are bound to each otherdirectly or via a hetero atom to form a monocyclic heterocyclic ring,which may be unsubstituted or substituted with an alkyl having 1 to 4carbon atoms or phenyl;

Z_(F) is carboxy, COOR1 (wherein R1 is a substituted or unsubstitutedalkyl having 1 to 4 carbon atoms or, phenyl), CONR2R3 (wherein each ofR2 and R3, which may be the same or different and independentlyrepresents hydrogen or an unsubstituted or substituted alkyl having 1 to4 carbon atoms), cyano, CH₂OR4 (wherein R4 is hydrogen, an unsubstitutedor substituted alkyl having 1 to 4 carbon atoms or, an unsubstituted orsubstituted acyl having 1 to 5 carbon atoms), hydroxy, OR5 (wherein R5is an unsubstituted or substituted alkyl having 1 to 4 carbon atoms or,an unsubstituted or substituted acyl having 1 to 5 carbon atoms,preferably an alkyl having 1 to 4 carbon atoms or an acyl having 1 to 5carbon atoms), NR6R7 (wherein each of R6 and R7, which may be the sameor different and independently is hydrogen, an alkyl having 1 to 4carbon atoms or an acyl having 1 to 5 carbon atoms), 5-tetrazolyl,chlorine or fluorine.

48) A β-di-substituted aminoketone derivative of formula [1F] describedin 1) above or a pharmacologically acceptable salt thereof, according to47) described above, wherein:

A_(F) and B_(F) are combined together to form an unsubstituted orsubstituted cyclopentan-1-one ring or to form an unsubstituted orsubstituted cyclopentan-1-one ring fused with a benzene or monocyclicaromatic heterocyclic ring;

each of X_(F) and Y_(F), which may be the same or different andindependently is an alkyl 1 to 6 carbon atoms or, X_(F) and Y_(F) arebound to each other directly or via a hetero atom to form a monocyclicheteroaryl ring, which may be unsubstituted or substituted with an alkylhaving 1 to 4 carbon atoms or phenyl;

Z_(F) is carboxy, COOR1′ (wherein R1′ is an alkyl having 1 to 4 carbonatoms), CONR2′R3′ (wherein R2′ and R3′ , which may be the same ordifferent and each is hydrogen or an alkyl having 1 to 4 carbon atoms),cyano or CH₂OR4′ (wherein R4′ is hydrogen, an alkyl having 1 to 4 carbonatoms or an acyl having 1 to 5 carbon atoms).

49) A β-di-substituted aminoketone derivative of formula [1F] describedin 1) above or a pharmacologically acceptable salt thereof, according to48) described above, wherein:

A_(F) and B_(F) are combined together to form a cyclopentan-1-one ringor indan-1-one ring;

X_(F) and Y_(F) are both ethyl, n-propyl or isopropyl; or, X_(F) andY_(F) are bound to each other directly or via a hetero atom to form apyrrolidine, piperidine, morpholine, 4-methylpiperazine or4-phenylpiperazine ring; and,

Z_(F) is carboxy, COOR1″ (wherein R1″ is methyl or ethyl), CONR2″R3″(wherein R2″ and R3″ , which may be the same or different and each ishydrogen, methyl or ethyl) or cyano.

50) A pharmaceutical composition comprising as an effective ingredient acyclopentanone derivative of formula [1A] according to 1) above or acyclopentanone derivative according to any one of 2) through 6)described above, or a pharmacologically acceptable salt thereof, whereinthe cyclopentanone derivative further includes:

(1) when Z1_(A) and Z2_(A) are hydrogen, X_(A) is S, Y_(A) is methyl orbenzyl and, Z3_(A) is methoxycarbonyl,

(2) when Z1_(A) and Z2_(A) are hydrogen, X_(A) is O or N, Y_(A) isbenzyl and, Z3_(A) is carboxy, methoxycarbonyl or ethoxycarbonyl;

(3) X_(A) is N or O, Z1_(A) and Z3_(A) are hydrogen and, Z2_(A) iscarboxy or methoxycarbonyl;

(4) X_(A) is O, Z1_(A) is hydroxy or a group derived therefrom, Z2_(A)is hydrogen and, Z3_(A) is amino or a group derived therefrom;

(5) X_(A) is S, Y1_(A) is phenyl, Z1_(A) is dimethoxymethyl and, Z2_(A)and Z3_(A) are hydrogen;

(6) X_(A) is O, Y1_(A) is methyl, Z1_(A) is 1-methoxy-1-phenylthiomethyland, Z2_(A) and Z3_(A) are hydrogen;

(7) Z1_(A) is S, SO or SO₂, Z2_(A) is hydroxy or a group derivedtherefrom and, Z3_(A) is hydrogen.

51) A composition for the treatment of central nervous disorderscomprising as an effective ingredient a cyclopentanone derivative offormula [1A] according to 1) above or a cyclopentanone derivativeaccording to any one of 2) through 6) described above, or apharmacologically acceptable salt thereof, wherein the cyclopentanonederivative further includes:

(1) when Z1_(A) and Z2_(A) are hydrogen, X_(A) is S, Y_(A) is methyl orbenzyl and, Z3_(A) is methoxycarbonyl,

(2) when Z1_(A) and Z2_(A) are hydrogen, X_(A) is O or N, Y_(A) isbenzyl and, Z3_(A) is carboxy, methoxycarbonyl or ethoxycarbonyl;

(3) X_(A) is N or O, Z1_(A) and Z3_(A) are hydrogen and, Z2_(A) iscarboxy or methoxycarbonyl;

(4) X_(A) is O, Z1_(A) is hydroxy or a group derived therefrom, Z2_(A)is hydrogen and, Z3_(A) is amino or a group derived therefrom;

(5) X_(A) is S, Y1_(A) is phenyl, Z1_(A) is dimethoxymethyl and, Z2_(A)and Z3_(A) are hydrogen;

(6) X_(A) is O, Y1_(A) is methyl, Z1_(A) is 1-methoxy-1-phenylthiomethyland, Z2_(A) and Z3_(A) are hydrogen;

(7) Z1_(A) is S, SO or SO₂, Z2_(A) is hydroxy or a group derivedtherefrom and, Z3_(A) is hydrogen.

52) A composition for the treatment of peripheral nervous disorderscomprising as an effective ingredient a cyclopentanone derivative offormula [1A] according to 1) above or a cyclopentanone derivativeaccording to any one of 2) through 6) described above, or apharmacologically acceptable salt thereof,wherein the cyclopentanonederivative further includes:

(1) when Z1_(A) and Z2_(A) are hydrogen, X_(A) is S, Y_(A) is methyl orbenzyl and, Z3_(A) is methoxycarbonyl,

(2) when Z1_(A) and Z2_(A) are hydrogen, X_(A) is O or N, Y_(A) isbenzyl and, Z3_(A) is carboxy, methoxycarbonyl or ethoxycarbonyl;

(3) X_(A) is N or O, Z1_(A) and Z3_(A) are hydrogen and, Z2_(A) iscarboxy or methoxycarbonyl;

(4) X_(A) is O, Z1_(A) is hydroxy or a group derived therefrom, Z2_(A)is hydrogen and, Z3_(A) is amino or a group derived therefrom;

(5) X_(A) is S, Y1_(A) is phenyl, Z1_(A) is dimethoxymethyl and, Z2_(A)and Z3_(A) are hydrogen;

(6) X_(A) is O, Y1_(A) is methyl, Z1_(A) is 1-methoxy-1-phenylthiomethyland, Z2_(A) and Z3_(A) are hydrogen;

(7) Z1_(A) is S, SO or SO₂, Z2_(A) is hydroxy or a group derivedtherefrom and, Z3_(A) is hydrogen.

53) A composition for promoting nerve cell differentiation comprising asan effective ingredient a cyclopentanone derivative of formula [1A]according to 1) above or a cyclopentanone derivative according to anyone of 2) through 6) described above, or a pharmacologically acceptablesalt thereof, wherein the cyclopentanone derivative further includes:

(1) when Z1_(A) and Z2_(A) are hydrogen, X_(A) is S, Y_(A) is methyl orbenzyl and, Z3_(A) is methoxycarbonyl,

(2) when Z1_(A) and Z2_(A) are hydrogen, X_(A) is O or N, Y_(A) isbenzyl and, Z3_(A) is carboxy, methoxycarbonyl or ethoxycarbonyl;

(3) X_(A) is N or O, Z1_(A) and Z3_(A) are hydrogen and, Z2_(A) iscarboxy or methoxycarbonyl;

(4) X_(A) is O, Z1_(A) is hydroxy or a group derived therefrom, Z2_(A)is hydrogen and, Z3_(A) is amino or a group derived therefrom;

(5) X_(A) is S, Y1_(A) is phenyl, Z1_(A) is dimethoxymethyl and, Z2_(A)and Z3_(A) are hydrogen;

(6) X_(A) is O, Y1_(A) is methyl, Z1_(A) is 1-methoxy-1-phenylthiomethyland, Z2_(A) and Z3_(A) are hydrogen;

(7) Z1_(A) is S, SO or SO₂, Z2_(A) is hydroxy or a group derivedtherefrom and, Z3_(A) is hydrogen.

54) A pharmaceutical composition comprising as an effective ingredient a2,3-di-substituted cyclopentanone derivative of formula [1B] describedin 1) above or a 2,3-di-substituted cyclopentanone derivative accordingto any one of 7) through 18) described above, or a pharmacologicallyacceptable salt thereof.

55) A composition for the treatment of central nervous disorderscomprising as an effective ingredient a 2,3-di-substitutedcyclopentanone derivative of formula [1B] described in 1) above or a2,3-di-substituted cyclopentanone derivative according to any one of 7)through 18) described above, or a pharmacologically acceptable saltthereof.

56) A composition for the treatment of peripheral nervous disorderscomprising as an effective ingredient a 2,3-di-substitutedcyclopentanone derivative of formula [1B] described in 1) above or a2,3-di-substituted cyclopentanone derivative according to any one of 7)through 18), or a pharmacologically acceptable salt thereof.

57) A composition for promoting nerve cell differentiation comprising asan effective ingredient a 2,3-di-substituted cyclopentanone derivativeof formula [1B] described in 1) above or a 2,3-di-substitutedcyclopentanone derivative according to any one of 7) through 18), or apharmacologically acceptable salt thereof.

58) A pharmaceutical composition comprising as an effective ingredient acyclopentenone derivative of formula [1C] described in 1) above or acyclopentenone derivative according to any one of 19) through 26), or apharmacologically acceptable salt thereof, wherein said cyclopentenonederivative further includes the cases that when X_(c) is O or NH, Z1_(c)and Z3_(c) are hydrogen and, Z2_(c) is hydrogen or, hydroxy or a groupderived therefrom.

59) A composition for the treatment of central nervous disorderscomprising as an effective ingredient a cyclopentenone derivative offormula [1C] described in 1) above or a cyclopentenone derivativeaccording to any one of 19) through 26) described above, or apharmacologically acceptable salt thereof, wherein said cyclopentenonederivative further includes the cases that when X_(c) is O or NH, Z1_(c)and Z3_(c) are hydrogen and, Z2_(c) is hydrogen or, hydroxy or a groupderived therefrom.

60) A composition for the treatment of peripheral nervous disorderscomprising as an effective ingredient a cyclopentenone derivative offormula [1C] described in 1) above or a cyclopentenone derivativeaccording to any one of 19) through 26) described above, or apharmacologically acceptable salt thereof, wherein said cyclopentenonederivative further includes the cases that when X_(c) is O or NH, Z1_(c)and Z3_(c) are hydrogen and, Z2_(c) is hydrogen or, hydroxy or a groupderived therefrom.

61) A composition for promoting nerve cell differentiation comprising asan effective ingredient a cyclopentenone derivative of formula [1C]described in 1) above or a cyclopentenone derivative according to anyone of 19) through 26) described above, or a pharmacologicallyacceptable salt thereof, wherein said cyclopentenone derivative furtherincludes the cases that when X_(c) is O or NH, Z1_(c) and Z3_(c) arehydrogen and, Z2_(c) is hydrogen or, hydroxy or a group derivedtherefrom.

62) A pharmaceutical composition comprising as an effective ingredient aketone derivative of formula [1D] according to 1) above or a ketonederivative according to any one of 26) through 38) described above, or apharmacologically acceptable salt thereof, wherein, when A_(D) and B_(D)are combined together to form a cyclobutane ring, the ketone derivativefurther includes (1) through (4):

(1) X_(D) is O, Y_(D) is methyl, n-octyl or n-hexadecyl and, Z_(D) ismethoxycarbonyl;

(2) X_(D) is O, Y_(D) is benzyl and, Z_(D) is benzyloxylmethyl;

(3) X_(D) is O, Y_(D) is p-methoxybenzyl and, Z_(D) isp-methoxybenzyloxymethyl; and,

(4) X_(D) is O, Y_(D) is trityl and Z_(D) is trityloxymethyl and whenA_(D) is an unsubstituted benzene ring and B_(D) is hydrogen, X_(D) isS, Y_(D) is methyl, ethyl or isopropyl and Z_(D) is carboxy.

63) A composition for the treatment of central nervous disorderscomprising as an effective ingredient a ketone derivative of formula[1D] according to 1) above or a ketone derivative according to any oneof 26) through 38) described above, or a pharmacologically acceptablesalt thereof, wherein, when A_(D) and B_(D) are combined together toform a cyclobutane ring, the ketone derivative further includes (1)through (4):

(1) X_(D) is O, Y_(D) is methyl, n-octyl or n-hexadecyl and, Z_(D) ismethoxycarbonyl;

(2) X_(D) is O, Y_(D) is benzyl and, Z_(D) is benzyloxylmethyl;

(3) X_(D) is O, Y_(D) is p-methoxybenzyl and, Z_(D) isp-methoxybenzyloxymethyl; and,

(4) X_(D) is O, Y_(D) is trityl and Z_(D) is trityloxymethyl and whenA_(D) is an unsubstituted benzene ring and B_(D) is hydrogen, X_(D) isS, Y_(D) is methyl, ethyl or isopropyl and Z_(D) is carboxy.

64) A composition for the treatment of peripheral nervous disorderscomprising as an effective ingredient a ketone derivative of formula[1D] according to 1) above or a ketone derivative according to any oneof 26) through 38) described above, or a pharmacologically acceptablesalt thereof, wherein, when A_(D) and B_(D) are combined together toform a cyclobutane ring, the ketone derivative further includes (1)through (4):

(1) X_(D) is O, Y_(D) is methyl, n-octyl or n-hexadecyl and, Z_(D) ismethoxycarbonyl;

(2) X_(D) is O, Y_(D) is benzyl and, Z_(D) is benzyloxylmethyl;

(3) X_(D) is O, Y_(D) is p-methoxybenzyl and, Z_(D) isp-methoxybenzyloxymethyl; and,

(4) X_(D) is O, Y_(D) is trityl and Z_(D) is trityloxymethyl and whenA_(D) is an unsubstituted benzene ring and B_(D) is hydrogen, X_(D) isS, Y_(D) is methyl, ethyl or isopropyl and Z_(D) is carboxy.

65) A composition for promoting nerve cell differentiation comprising asan effective ingredient a ketone derivative of formula [1D] accordingto 1) above or a ketone derivative according to any one of 26) through38) described above, or a pharmacologically acceptable salt thereof,wherein, when A_(D) and B_(D) are combined together to form acyclobutane ring, the ketone derivative further includes (1) through(4):

(1) X_(D) is O, Y_(D) is methyl, n-octyl or n-hexadecyl and, Z_(D) ismethoxycarbonyl;

(2) X_(D) is O, Y_(D) is benzyl and, Z_(D) is benzyloxylmethyl;

(3) X_(D) is O, Y_(D) is p-methoxybenzyl and, Z_(D) isp-methoxybenzyloxymethyl; and,

(4) X_(D) is O, Y_(D) is trityl and Z_(D) is trityloxymethyl and whenA_(D) is an unsubstituted benzene ring and B_(D) is hydrogen, X_(D) isS, Y_(D) is methyl, ethyl or isopropyl and Z_(D) is carboxy.

66) A pharmaceutical composition comprising as an effective ingredient acompound of formula [1E] according to 1) above or a pharmacologicallyacceptable salt thereof.

67) A composition for the treatment of central nervous disorderscomprising as an effective ingredient a compound of formula [1E]according to 1) above or a pharmacologically acceptable salt thereof.

68) A composition for the treatment of peripheral nervous disorderscomprising as an effective ingredient a compound of formula [1E]according to 1) above or a pharmacologically acceptable salt thereof.

69) A composition for promoting nerve cell differentiation comprising asan effective ingredient a compound of formula [1E] according to 1) aboveor a pharmacologically acceptable salt thereof.

70) A pharmaceutical composition comprising as an effective ingredient aβ-di-substituted aminoketone derivative of formula [1F] according to 1)above or β-di-substituted aminoketone derivative according to any of39)˜49) described above, or a pharmacologically acceptable salt thereof,wherein, when A_(F) is an unsubstituted benzene ring, theβ-di-substituted aminoketone derivative further includes those whereinB_(F)is hydrogen, X_(F) is bound directly to Y_(F) to form a piperidinering and, Z_(F) is carboxy.

71) A composition for the treatment of central nervous disorderscomprising as an effective ingredient a β-di-substituted aminoketonederivative of formula [1F] according to 1) above or a β-di-substitutedaminoketone derivative according to any of 39)˜49) described above, or apharmacologically acceptable salt thereof, wherein, when A_(F) is anunsubstituted benzene ring, the β-di-substituted aminoketone derivativefurther includes those wherein B_(F) is hydrogen, X_(F) is directlybound to Y_(F) to form a piperidine ring and, Z_(F) is carboxy.

72) A composition for the treatment of peripheral nervous disorderscomprising as an effective ingredient a β-di-substituted aminoketonederivative of formula [1F] according to 1) above or a β-di-substitutedaminoketone derivative according to any of 39)˜49) described above, or apharmacologically acceptable salt thereof, wherein, when A_(F) is anunsubstituted benzene ring, the β-di-substituted aminoketone derivativefurther includes those wherein B_(F) is hydrogen, X_(F) is directlybound to Y_(F) to form a piperidine ring and, Z_(F) is carboxy.

73) A composition for promoting nerve cell differentiation comprising asan effective ingredient a β-di-substituted aminoketone derivative offormula [1F] according to 1) above or a β-di-substituted aminoketonederivative according to any of 39)˜49) described above, or apharmacologically acceptable salt thereof, wherein, when A_(F) is anunsubstituted benzene ring, the β-di-substituted aminoketone derivativefurther includes those wherein B_(F) is hydrogen, X_(F) is directlybound to Y_(F) to form a piperidine ring and, Z_(F) is carboxy.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows the infrared absorption spectrum of NA32176A (compound offormula [1E]) measured using a potassium bromide tablet.

FIG. 2 shows the hydrogen nuclear magnetic resonance spectrum ofNA32176A (compound of formula [1E]) measured in heavy water.

FIG. 3 shows the hydrogen nuclear magnetic resonance spectrum ofNA32176A (compound of formula [1E]) measured in heavy water.

BEST MODE FOR CARRYING OUT THE INVENTION

The compounds of the present invention represented by formulas [1A],[1B], [1C], [1D], [1E] and [1F] exhibit a neuron differentiationpromoting activity and can be used as medicaments for the treatment ofnerve disturbances in the central and peripheral nervous systems.

The compounds of the present invention will be described below in moredetail.

[A] Compounds of formula [1A]

In the general formula [1A], X_(A) is preferably O, S or SO, mostpreferably S.

The straight or branched aliphatic group having 1 to 20 carbon atoms,which is shown by Y_(A) in the general formula [1A], refers to an alkylor alkenyl having 1 to 20 carbon atoms, preferably an alkyl having 1 to6 carbon atoms, e.g., methyl, ethyl, n-propyl, n-butyl, n-pentyl,n-hexyl, isopropyl or tert-butyl, more preferably a straight aliphaticgroup having 1 to 4 carbon atoms, most preferably, ethyl. The aliphaticgroup may be either unsubstituted or substituted. Where the aliphaticgroup is substituted, 1 to 6, preferably 1 to 3 substituents may bepresent on the aliphatic group. Examples of such substituents arecarboxy or a group derived therefrom, amino or a group derivedtherefrom, or hydroxy or a group derived therefrom.

In the aromatic hydrocarbon and monocyclic aromatic heterocyclic ringhaving 3 to 6 carbon atoms in the general formula [1A], the aromatichydrocarbon group is preferably a benzene ring and the monocyclicaromatic heterocyclic ring refers to a 5- or 6-membered ring containinga nitrogen, oxygen or sulfur atom. Where these groups are substituted,examples of the substituents are the same as given for the aliphaticgroup.

The group derived from carboxy includes a carboxy-functional group suchas an esterified or amidated carboxy group, cyano, hydroxymethyl oraminomethyl formed by reducing these functional groups, and functionalgroups derived therefrom by modification like acylation of thefunctional groups. Preferably, the carboxy and the group derivedtherefrom include carboxy, COOR1 (wherein R1 is a substituted orunsubstituted alkyl, alkenyl or alkynyl having 1 to 4 carbon atoms), andCOW (wherein W is an unsubstituted or substituted saturated heterocyclicring. The alkyl, alkenyl or alkynyl shown by R1 for COOR1 may bestraight, branched or cyclic. When R1 is substituted 1 to 6, preferably1 to 3 substituents may be present on R1, and examples of thesubstituent are a halogen, hydroxy, carboxy, methoxycarbonyl, cyano andacetylamino. R1 is preferably unsubstituted. Examples of the alkyl groupare methyl, ethyl, ethylene, n-propyl, isopropyl, cyclopropyl, n-butyl,isobutyl, tert-butyl and cyclobutyl, preferably methyl, ethyl, ethyleneand n-propyl, more preferably methyl. Examples of the alkenyl group arevinyl, 2-propenyl, isopropenyl and 2-butenyl. A typical example of thealkynyl group is 2-propenyl. W represents a heterocyclic ring,preferably a saturated heterocyclic ring, more preferably an azetidine,piperidine, pyrrolidine, morpholine or piperazine ring. Theseheterocyclic rings may be linked to carbonyl via a carbon or nitrogenatom, preferably linked to carbonyl via nitrogen. Where the heterocyclicring is substituted, 1 to 4, preferably 1 to 2 substituents may bepresent on each ring. Preferred examples of the substituents are carboxyand a group derived therefrom, more preferably carboxy and COOR11(wherein R11 is an unsubstituted or substituted alkyl having 1 to 4carbon atoms; in this case, examples of the alkyl and the substituentswhere the alkyl is substituted are the same as in R1 described above).

Examples of the group derived from amino include such functional groupsthat amino is alkylated, acylated or sulfonated, nitro, hydroxyamino,imino and a heterocyclic group containing the nitrogen atom of amino,preferably a group shown by NR2R3 (wherein each of R2 and R3, which maybe different or the same, independently represents hydrogen, anunsubstituted or substituted alkyl having 1 to 4 carbon atoms or anunsubstituted or substituted acyl having 1 to 5 carbon atoms). In thegroup shown by NR2R3, the alkyl for R2 and R3 and the substituents wherethe alkyl is substituted are the same as in R1. The acyl for R2 and R3may be straight, branched, cyclic, saturated or unsaturated. Where theacyl is substituted, the substituents are the same as in R1. Morepreferably, the amino-derived group is represented by NHCOR12 (whereinR12 is an alkyl having 1 to 4 carbon atoms and examples of R12 are thesame as in R1), and most preferably, R12 is methyl.

Examples of the group derived from hydroxy include a functional group inwhich hydroxy is alkylated or acylated, e.g., OCOR14 (wherein thealkylated functional group in R14 is an unsubstituted or substitutedalkyl and examples of the alkyl are the same as in R1; and the acylatedfunctional group in R14 is an unsubstituted or substituted acyl andexamples of the acyl are the same as in R2), a keto and a halogen.

Each of Z1_(A), Z2_(A) and Z3_(A) in the compounds of formula [1A]represents carboxy or a group derived therefrom, an unsubstituted orsubstituted alkyl having 1 to 4 carbon atoms, hydroxy or a group derivedtherefrom, amino or a group derived therefrom, sulfate or a groupderived therefrom, phosphate or a group derived therefrom, a monocyclicaromatic heterocyclic ring, a halogen or hydrogen; or Z2_(A) and Z3_(A)are combined together to form a substituted or unsubstituted aromatichydrocarbon or a aromatic heterocyclic ring; in this case Z1_(A) iscarboxy or a group derived therefrom, an unsubstituted or substitutedalkyl having 1 to 4 carbon atoms, hydroxy or a group derived therefrom,amino or a group derived therefrom, a halogen or hydrogen. Examples ofthe group derived from sulfate are groups from sulfonamide derivatives,such as SO₂NH₂, SO₂NHCH₃, SO₂N(CH₃)₂ and SO₂NHCOCH₃. Examples of thegroup derived from phosphate are P(O)(OH)H, P(O)(OH)(NH₂) andP(O)(OH)CH(OCH₃)₂. Examples of the groups derived from carboxy, hydroxyand amino are the same as described above. Examples of the group derivedfrom amino further include NHSO₂Ph, NHCOCF₃, NHCOC₂F₅, NHSO₂CF₃ andNHSO₂C₂F₅. Preferred examples of Z1_(A), Z2_(A) and Z3_(A) includecarboxy, COOR4 (wherein R4 is an unsubstituted or substituted alkylhaving 1 to 4 carbon atoms), CONR5R6 (wherein each of R5 and R6, whichmay be different or the same, independently represents hydrogen or asubstituted or unsubstituted alkyl having 1 to 4 carbon atoms), cyano,hydroxy, OR7 (wherein R7 is an unsubstituted or substituted alkyl having1 to 4 carbon atoms or an unsubstituted or substituted acyl having 1 to5 carbon atoms), NR8R9 (wherein each of R8 and R9, which may be the sameor different, independently represents hydrogen, an unsubstituted orsubstituted alkyl having 1 to 4 carbon atoms or an unsubstituted orsubstituted acyl having 1 to 5 carbon atoms), CH₂OR10 (wherein R10 ishydrogen, an unsubstituted or substituted alkyl having 1 to 4 carbonatoms or an unsubstituted or substituted acyl having 1 to 5 carbonatoms), 5-tetrazolyl, a halogen or hydrogen. Examples of the aforesaidunsubstituted or substituted alkyl having 1 to 4 carbon atoms, the alkylshown by R4, R5, R6, R7, R8, R9 or R10 and the substituents when thesegroups are substituted are the same as in R1. Examples of the acyl shownby R7, R8, R9 or R10 and the substituents when these groups aresubstituted are the same as in R2. Specific examples of the acyl areacetyl, propionyl, acroyl, propioloyl, n-butyryl, isobutyryl, crotonoyl,valeryl, isovaleryl and pivaloyl, preferably acetyl, propionyl, acroyland propioloyl, more preferably acetyl. A particularly preferredcombination of R8 and R9 is that R8 is hydrogen and R9 is acetyl.Examples of the halogen are fluorine, chlorine, bromine and iodine,preferably fluorine and chlorine. Preferred examples of the substituentsfor Z1_(A), Z2_(A) and Z3_(A) are the case where one or two aresubstituents other than hydrogen, more preferably, substituents such ascarboxy, COOR4, OCOR13 (wherein R13 is an alkyl having 1 to 4 carbonatoms and examples of the alkyl are the same as in those of R1), hydroxyand CH₂OR10, most preferably, carboxy, methoxycarbonyl, hydroxymethyl,hydroxy and acetyloxymethyl.

Examples of the aromatic hydrocarbon formed by combining Z2_(A) andZ3_(A) are a benzene ring and a naphthalene ring. Examples of thearomatic heterocyclic ring formed by Z2_(A) and Z3_(A) are a 6-memberedheteroaryl such as a pyridine, pyrazine or pyrimidine ring, and a5-membered aromatic heterocyclic ring such as a thiophene, pyrrole,furan, oxazole, thiazole, isoxazole, isothiazole or azole ring.Preferably, the group formed by Z2_(A) and Z3_(A) is an aromatichydrocarbon, more preferably a benzene ring. When the ring issubstituted, examples of the substituents are the same as in those of Z.Preferred examples of the substituents include an alkyl having 1 to 4carbon atoms, preferably, methyl, ethyl, n-propyl and isopropyl, whichmay be unsubstituted or substituted with a halogen (e.g., fluorine) suchas trifluoromethyl; an alkyloxy having 1 to 4 carbon atoms such asmethoxy and ethoxy; nitro, and a halogen, e.g., fluorine, chlorine orbromine.

[B] Compounds of formula [1B]

In the compounds of the present invention represented by formula [1B],X_(B) ?? is preferably S, O or SO, most preferably S.

The straight or branched aliphatic hydrocarbon group having 7 to 20carbon atoms, which is shown by YB, refers to an alkyl or alkenyl grouphaving 7 to 20 carbon atoms. Examples of the alkyl or alkenyl aren-pentyl, n-octyl, n-nonyl, n-decanyl, n-undecanyl, n-dodecanyl,n-tridecanyl, n-tetradecanyl, n-pentadecanyl, n-dodecanyl,n-hexadecanyl, n-pentadecanyl and n-octadecanyl, preferably an alkylhaving 7 to 15 carbon atoms, most preferably n-dodecyl. The aliphatichydrocarbon group may be unsubstituted or substituted. Where thealiphatic hydrocarbon group is substituted, the aliphatic group mayhave, for example, 1 to 6, preferably 1 to 3 substituents thereon. Assuch substituents, there are carboxy or a group derived therefrom, aminoor a group derived therefrom, hydroxy or a group derived therefrom.

The group derived from carboxy includes a carboxy-functional group suchas an esterified or amidated carboxy group, cyano, hydroxymethyl oraminomethyl formed by reducing these functional groups, and functionalgroups derived therefrom by modification like acylation of thefunctional groups. Preferably, the carboxy and the group derivedtherefrom include carboxy and COOR6 (wherein R6 is an unsubstituted orsubstituted alkyl, alkenyl or alkynyl having 1 to 4 carbon atoms). Thealkyl, alkenyl or alkynyl shown by R6 in COOR6 may be straight, branchedor cyclic. Where R6 is substituted, examples of the substituent are ahalogen, hydroxy, carboxy, methoxycarbonyl, cyano and acetamido. R6 ispreferably unsubstituted. Examples of the alkyl group are methyl, ethyl,ethylene, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl,tert-butyl and cyclobutyl, preferably methyl, ethyl, ethylene andn-propyl. Examples of the alkenyl group are vinyl, 2-propenyl,isopropenyl and 2-butenyl. A typical example of the alkynyl group is2-propenyl.

Examples of the group derived from amino include such functional groupsthat amino is alkylated, acylated or sulfonated, nitro, hydroxyamino,imino and a heterocyclic group containing the nitrogen atom of amino,preferably a group shown by NR7R8 (wherein each of R7 and R8, which maybe different or the same, independently represents hydrogen, anunsubstituted or substituted alkyl having 1 to 4 carbon atoms or anunsubstituted or substituted acyl having 1 to 5 carbon atoms). In thegroup shown by NR7R8, the alkyl for R7 and R8 and the substituents wherethe alkyl is substituted are the same as in R6. The acyl for R7 and R8may be straight, branched, cyclic, saturated or unsaturated. Where theacyl is substituted, the substituents are the same as in R6.Representative examples of the acyl are acetyl, propionyl, acroyl,propioloyl, n-butyryl, isobutyryl, crotonoyl, valeryl, isovaleryl andpivaloyl, preferably acetyl, propionyl, acroyl and propioloyl, morepreferably acetyl. A particularly preferred combination of R7 and R8 isthat R7 is hydrogen and R8 is acetyl.

Examples of the group derived from hydroxy include a functional group inwhich hydroxy is alkylated or acylated, e.g., OCOR14 (wherein thealkylated functional group in R14 is an unsubstituted or substitutedalkyl and examples of the alkyl are the same as in R6; and the acylatedfunctional group in R14 is an unsubstituted or substituted acyl andexamples of the acyl are the same as in R7), a keto and a halogen.

In the compounds of general formula [1B], the straight or branchedaliphatic group having 1 to 6 carbon atoms, which is substituted withCOW, is exemplified by methyl, ethyl, n-propyl, n-butyl, n-pentyl,n-hexyl, isopropyl and tert-butyl, preferably a straight aliphatic grouphaving 1 to 4 carbon atoms, more preferably ethyl. In the aliphaticgroup, at least one hydrogen, preferably one hydrogen, should besubstituted with COW. W represents an unsubstituted or substitutedheteroaryl or a saturated aromatic heterocyclic ring, preferably asaturated aromatic heterocyclic ring, more preferably an azetidine,piperidine, pyrrolidine, piperazine or morpholine ring. Theseheterocyclic rings may be linked to carbonyl via a carbon or nitrogenatom, preferably via nitrogen. Where the heterocyclic ring issubstituted, each ring may contain 1 to 4, preferably 1 to 2substituents thereon. Preferred examples of the substituents arecarboxy, a hydroxyalkyl having 1 to 4 carbon atoms, phenyl or COOR9(wherein R9 is an unsubstituted or substituted alkyl having 1 to 4carbon atoms; in this case, examples of the alkyl and the substituentswhere the alkyl is substituted are the same as in R6 described above).Examples of the hydroxyalkyl are 2-hydroxyethyl, 3-hydroxypropyl and4-hydroxybutyl, preferably 2-hydroxyethyl. COOR9 is preferablytert-butoxycarbonyl. In the COOR9, at least one hydrogen, preferably onehydrogen may be substituted with amino or a group derived therefrom.Examples of the group derived from amino are the same as describedabove, preferably NR10R11 (wherein each of R10 and R11, which may be thesame or different, independently represents hydrogen, an unsubstitutedor substituted alkyl having 1 to 4 carbon atoms or an unsubstituted orsubstituted acyl having 1 to 5 carbon atoms). In the group shown byNR10R11, examples of the alkyl and the substituents where the alkyl issubstituted are the same as those given for R6. In the group shown byNR10R11, the acyl for R10 and R11 may be straight, branched, cyclic,saturated or unsaturated. Where the acyl is substituted, thesubstituents are the same as those given for R6, preferably NHCOR12(wherein R12 is an alkyl having 1 to 4 carbon atoms and examples of thealkyl are the same as those given for R6).

In the compounds of general formula [1B], examples of the straight orbranched aliphatic group having 1 to 6 carbon atoms and substituted withNHCOV1 are methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl,isopropyl and tert-butyl, preferably a straight aliphatic group having 1to 4 carbon atoms, more preferably ethyl. In the aliphatic group, atleast one hydrogen, preferably one hydrogen, should be substituted withNHCOV1. V represents an alkyl having 2 to 5 carbon atoms, which contains4 to 11 halogen atoms. Examples of the halogen are fluorine, chlorine,bromine and iodine, preferably fluorine. Specific examples of theNHCOV1-substituted alkyl are tetrafluoroethyl, heptafluoro-n-propyl,nonafluoro-n-butyl and undecafluoro-n-pentyl. In this aliphatichydrocarbon group, at least one hydrogen, preferably one hydrogen may besubstituted with carboxy or a group derived therefrom. Examples of thecarboxy-derived group are the same as those described above, preferablycarboxy or COOR13 (wherein R13 is an unsubstituted or substituted alkylhaving 1 to 4 carbon atoms, an alkenyl or an alkynyl, and examples ofthese groups are the same as those given for R6), more preferablycarboxy.

In Y_(B) of the compounds represented by general formula [1B], the arylhaving 3 to 6 carbon atoms refers to, e.g., a benzene ring and themonocyclic aromatic heterocyclic ring having 3 to 6 carbon atoms refersto a 5- or 6-membered ring containing nitrogen, oxygen or sulfur. Wherethe aromatic hydrocarbon ring or monocyclic aromatic heterocyclic ringis substituted, examples of such substituents are the same as thosegiven for the aliphatic group above.

In Y_(B) in the compounds represented by general formula [1B], thestraight or branched aliphatic group having 1 to 6 carbon atoms, whichis substituted with a monocyclic aromatic heterocyclic ring, isexemplified by methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl,isopropyl and tert-butyl, preferably a straight aliphatic group having 1to 4 carbon atoms, more preferably ethyl and n-propyl. In the aliphatichydrocarbon group, at least one hydrogen, preferably one hydrogen,should be substituted with monocyclic aromatic heterocyclic ring.Examples of the monocyclic aromatic heterocyclic ring are a pyridine,pyrazine, pyrimidine, indole, pyrrole, imidazole, triazole, tetrazole,furan and thiophene ring, preferably pyridine or tetrazole. Theseheterocyclic rings may be linked to the aliphatic group via carbon ornitrogen, preferably via carbon. Where the heterocyclic ring issubstituted, each ring may contain 1 to 4, preferably 1 to 2substituents thereon. Examples of the substituents are an alkyl having 1to 4 carbon atoms, preferably methyl. In this aliphatic group, at leastone hydrogen, preferably one hydrogen may be substituted with amino or agroup derived therefrom. Examples of the group derived from amino arethe same as described above, preferably NR15R16 (wherein each of R15 andR16, which may be the same or different, independently representshydrogen, an unsubstituted or substituted alkyl having 1 to 4 carbonatoms or an unsubstituted or substituted acyl having 1 to 5 carbonatoms). In the group shown by NR15R16, examples of the alkyl and thesubstituents where the alkyl is substituted are the same as those givenfor R6. The acyl may be straight, branched, cyclic, saturated orunsaturated. Where the acyl is substituted, the substituents are thesame as those given for R6, preferably NHCOR17 (wherein R17 is an alkylhaving 1 to 4 carbon atoms and examples of the alkyl are the same asthose given for R6).

In the compounds represented by general formula [1B], Z_(B) is carboxyor a group derived therefrom, sulfate or a group derived therefrom,phosphate or a group derived therefrom, an unsubstituted or substitutedalkyl having 1 to 4 carbon atoms, hydroxy, OR1 (wherein R1 is anunsubstituted or substituted alkyl having 1 to 4 carbon atoms or anunsubstituted or substituted acyl having 1 to 5 carbon atoms), NHCOR2(wherein R2 is an unsubstituted or substituted alkyl having 1 to 4carbon atoms), NHSO₂R2′ (wherein R2′ is an unsubstituted or substitutedalkyl having 1 to 4 carbon atoms or phenyl), a monocyclic aromaticheterocyclic ring, a halogen or hydrogen. Examples of thecarboxy-derived group are the same as those described above. Examples ofthe group derived from sulfate are groups from sulfonamide derivatives,such as SO₂NH₂, SO₂NHCH₃, SO₂N(CH₃)₂ and SO₂NHCOCH₃. Examples of thegroup derived from phosphate are P(O)(OH)H, P(O)(OH)(NH₂) andP(O)(OH)CH(OCH₃)₂. Examples of the alkyl having 1 to 4 carbon atoms, thealkyl shown by R1, R2 and R2′ and the substituents when these alkylgroups are substituted are the same as those given for R6. Examples ofthe acyl in R1 and the substituents when the acyl is substituted are thesame as those given for R7. Examples of NHCOR2 are NHCOCH₃, NHCOCF₃ andNHCOC₂F₅. Examples of NHSO₂R2′ are NHSO₂Ph, NHSO₂CF₃ and NHSO₂C₂F₅. Apreferred example of the monocyclic heteroaryl is 5-tetrazolyl. InZ_(R), examples of the halogen are fluorine, chlorine, bromine andiodine, preferably fluorine and chlorine. Preferred examples of Z arecarboxy, COOR3 (wherein R3 is an unsubstituted or substituted alkylhaving 1 to 4 carbon atoms and examples of the alkyl and substituents onthe alkyl are those given for R6), CH₂OR4 (wherein R4 is anunsubstituted or substituted alkyl having 1 to 4 carbon atoms andexamples of the alkyl and substituents on the alkyl are those given forR6), and CH₂OCOR5 (wherein R5 is an unsubstituted or substituted alkylhaving 1 to 4 carbon atoms and examples of the alkyl and substituents onthe alkyl are those given for R6), more preferably, carboxy,methoxycarbonyl, hydroxymethyl and acetyloxymethyl.

[C] Compounds of formula [1C]

In the present invention, ring A in the compounds represented by generalformula [1C] represents a 2-cyclopenten-1-one ring, which includes casesthat the Y_(c)—X_(c)—CH₂ moiety is bound to the carbon with a doublebond and the carbon with a single bond.

In the compounds of the present invention represented by formula [1C],X_(c) is preferably S, O or SO, most preferably S.

In Y_(c) in the compounds represented by general formula [1C], thestraight or branched aliphatic group having 1 to 6 carbon atoms includesan alkyl or an alkenyl. Examples of the alkyl are methyl, ethyl,n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl and tert-butyl. Examplesof the alkenyl are vinyl, 2-propenyl, isopropenyl and 2-butenyl.Preferably the aliphatic hydrocarbon group is an alkyl having 1 to 4carbon atoms, more preferably ethyl. The aliphatic hydrocarbon group maybe unsubstituted or substituted. Where the aliphatic hydrocarbon groupis substituted, it may contain 1 to 6, preferably 1 to 4 substituents.As such substituents, there are carboxy or a group derived therefrom,amino or a group derived therefrom and, hydroxy or a group derivedtherefrom. The aromatic hydrocarbon ring or monocyclic aromaticheterocyclic ring having 3 to 6 carbon atoms refers to an aromatichydrocarbon ring such as a benzene ring and a aromatic heterocyclic ringsuch as a 5- or 6-membered ring containing nitrogen, oxygen or sulfur.Where the aromatic hydrocarbon ring or aromatic heterocyclic ring issubstituted, examples of such substituents are the same as those givenfor the aliphatic hydrocarbon group.

The group derived from carboxy includes a carboxy-functional group suchas an esterified or amidated carboxy group, cyano, hydroxymethyl oraminomethyl formed by reducing these functional groups, and functionalgroups derived therefrom by modification like acylation or alkylation ofthe functional groups. Preferably, the carboxy and the group derivedtherefrom include carboxy, COOR1 (wherein R1 is an unsubstituted orsubstituted alkyl or alkenyl having 1 to 4 carbon atoms), CONR2R3(wherein each of R2 and R3, which may be different or the same,independently represents hydrogen or a substituted or unsubstitutedalkyl having 1 to 4 carbon atoms), and COW (W represents unsaturated orsaturated heterocyclic ring). Herein, the alkyl shown by R1 for COOR1may be straight, branched or cyclic. Examples of the alkyl group aremethyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl,tert-butyl and cyclobutyl, preferably methyl, ethyl, and n-propyl, andmore preferably methyl. Examples of the alkenyl are vinyl, 2-propenyl,isopropenyl and 2-butenyl. When substituted, for example, 1 to 6,preferably 1 to 3 substituents may be present. Examples of thesubstituents are a halogen, hydroxy, thiol, carboxy, methoxycarbonyl,acetyloxy, acetylthio, cyano and acetylamino. Examples of the halogenare bromine, chlorine and fluorine. Preferably, the substituent on R1 isunsubstituted.

Where the alkyl shown by R2 or R3 and its substituent(s) aresubstituted, examples of such substituents are the same as those givenfor R1.

Preferably W represents a saturated heterocyclic ring, more preferably,an azetidine, piperidine, pyrrolidine, piperazine or morpholine ring.These heterocyclic rings may be linked to carbonyl via carbon ornitrogen, preferably linked to carbonyl via nitrogen. Where theheterocyclic ring is substituted, 1 to 4, preferably 1 to 2 substituentsmay be present on each ring. Examples of the substituents are carboxy ora group derived therefrom and amino or a group derived therefrom.Examples of these groups are described in the specification.

Examples of the group derived from amino include such functional groupsthat amino is alkylated or acylated, nitro, hydroxyamino, imino and aheterocyclic group containing the nitrogen atom of amino, preferably agroup shown by NR4R5 (wherein each of R4 and R5, which may be differentor the same, independently represents hydrogen, an unsubstituted orsubstituted alkyl having 1 to 4 carbon atoms or an unsubstituted orsubstituted acyl having 1 to 5 carbon atoms). In the group shown byNR4R5, the alkyl for R4 and R5 and the substituents where the alkyl issubstituted are the same as those in R1. The acyl for R4 and R5 may bestraight, branched, cyclic, saturated or unsaturated. Representativeexamples of the acyl are acetyl, propionyl, acroyl, propioloyl,n-butyryl, isobutyryl, crotonoyl, valeryl, isovaleryl and pivaloyl.Where the acyl is substituted, the substituents are the same as those inR1. Preferably, the amino-derived group is NHCOR14 (wherein R14 is analkyl having 1 to 4 carbon atoms in which hydrogen(s) may be substitutedwith fluorine(s); examples of the alkyl are the same as those in R1).The number of fluorine atoms which may be substituted is 1 to 9,preferably 1 to 7. Most preferably, R14 is methyl.

Examples of the group derived from hydroxy include a functional group inwhich hydroxy is alkylated or acylated, a keto and a halogen, preferablyOCOR15 (wherein R15 is an alkyl having 1 to 4 carbon atoms and examplesof the alkyl are the same as those in R1).

In the cyclopentenone derivatives of general formula [1C], each ofZ1_(c), Z2_(c) and Z3_(c) represents carboxy or a group derivedtherefrom, an unsubstituted or substituted alkyl or alkenyl having 1 to4 carbon atoms, hydroxy or a group derived therefrom, amino or a groupderived therefrom, a monocyclic aromatic heterocyclic ring, a halogen orhydrogen. Examples of the group derived from carboxy, amino or hydroxyare the same as described above. Examples of the alkyl and alkenyl andsubstituents when the alkyl and alkenyl are substituted are the same asthose given for A. Preferred examples of Z1_(c), Z2_(c) and Z3_(c) arecarboxy, COOR7 (wherein R7 is an unsubstituted or substituted alkylhaving 1 to 4 carbon atoms), cyano, hydroxy, CH2OR10 (wherein R10 is ahydrogen, an unsubstituted or substituted alkyl having 1 to 4 carbonatoms, or an unsubstituted or substituted acyl having 1 to 5 carbonatoms), OCOR11 (wherein R11 is an unsubstituted or substituted alkylhaving 1 to 4 carbon atoms), NR12R13 (wherein each of R12 and R13, whichmay be different or the same, independently represents a hydrogen, anunsubstituted or substituted alkyl having 1 to 4 carbon atoms, or anunsubstituted or substituted acyl having 1 to 5 carbon atoms),5-tetrazolyl, chlorine, fluorine, or hydrogen. The alkyl for R7, R8, R9,R10, R11, R12 and R13 and substituents when the alkyl is substituted arethe same as those given for R1. Further, the acyl for R10, R12 and R13and substituents when the acyl is substituted are the same as thosegiven for R4. Preferred combination of R12 and R13 is that R12 is ahydrogen and R13 is acetyl. Examples of the halogen are fluorine,chlorine, bromine and iodine, preferably fluorine and chlorine.Preferred examples of substituents Z1_(c), Z2_(c) and Z3_(c) are thecase that all of the substituents are hydrogen, or that one or two aresubstituents other than hydrogen. More preferred examples of thesubstituents are, except for hydrogen, carboxy, COOR7′ (wherein R7′ isan alkyl having 1 to 4 carbon atoms) and CH₂OR10′ (wherein R10′ ishydrogen, an unsubstituted or substituted acyl having 1 to 5 carbonatoms). Examples of R7′ are the same as those given for R1. Examples ofthe acyl in R10′ are the same as those given for R4, most preferably,carboxy, methoxycarbonyl, hydroxymethyl and acetyloxymethyl.

[D] Compounds of formula [1D]

In the ketone derivative of the present invention represented by generalformula [1D], the unsubstituted or substituted aliphatic hydrocarbongroup having 1 to 4 carbon atoms, which is shown by A_(D), refers to analkyl or alkenyl having 1 to 4 carbon atoms which may optionally besubstituted. Examples of the alkyl group are methyl, ethyl, n-propyl,n-butyl, isopropyl, cyclopropyl and tert-butyl. Examples of the alkenylare vinyl, 2-propenyl, isopropenyl and 2-butenyl. Preferably, thealiphatic hydrocarbon group is exemplified by methyl, ethyl, n-propyland isopropyl, more preferably methyl. The aliphatic hydrocarbon groupmay be unsubstituted or substituted. When the aliphatic group issubstituted, for example, 1 to 6, preferably 1 to 3 substituents may bepresent. Examples of the substituents are a halogen, hydroxy, thiol,carboxy, methoxycarbonyl, acetoxy, acetylthio, cyano and acetylamino.Examples of the halogen are bromine, chlorine and fluorine. Preferably,the aliphatic hydrocarbon group is unsubstituted.

The unsubstituted or substituted aromatic hydrocarbon ring, aromaticheterocyclic ring or saturated heterocyclic ring shown by A_(D) in thecompounds of general formula [1D] is exemplified by a benzene,1-naphthalene, 2-naphthalene, thiophene, furan, pyrrole, imidazole,oxazole, pyrazole, isoxazole, pyridine, pyrazine, indane, quinoline,isoquinoline, quinazoline, coumarine, pyrrolidine, piperidine orpiperazine ring, preferably a benzene ring and a monocyclic aromaticheterocyclic ring, more preferably a benzene ring. These rings may beunsubstituted or substituted. When substituted, 1 to 6, preferably 1 to3 substituents may be present on each ring. Examples of the substituentsinclude an alkyl having 1 to 4 carbon atoms, a halogen, hydroxy, analkyloxy having 1 to 4 carbon atoms, amino, a monoalkylamino ordialkylamino having 1 to 4 carbon atoms, thiol, carboxy, analkyloxycarbonyl having 1 to 4 carbon atoms, an acyloxy having 1 to 5carbon atoms, an acylthio having 1 to 5 carbon atoms, an acylaminohaving 1 to 5 carbon atoms, cyano and trifluoromethyl. Examples of thehalogen are bromine, chlorine and fluorine. Examples of the alkyl having1 to 4 carbon atoms and the alkyl moiety in the acyl having 1 to 5carbon atoms are the same as those given for A. Preferred examples ofA_(D) are those unsubstituted, or those substituted with methyl,methoxy, methoxycarbonyl, nitro, cyano, a halogen or trifluoromethyl,for 1 to 3 hydrogen atoms.

In the ketone derivatives of general formula [1D], examples of theunsubstituted or substituted aliphatic group B_(D) having 1 to 4 carbonatoms are the same as those given for A_(D), preferably hydrogen ormethyl.

In the ketone derivatives of general formula [1D], A_(D) and B_(D) arecombined together to form an unsubstituted or substitutedcycloalkan-1-one ring having 3 to 7 carbon atoms (provided that a ringof 5 carbon atoms is excluded) and examples of such a ring include acyclopropanone, cyclobutanone, cyclohexanone and cycloheptanone ring,preferably a cyclobutanone and cyclohexanone ring. The cycloalkan-1-onering may be nsubstituted or substituted, except for the substitution ingeneral formula [1D]. When the ring is substituted, 1 to 4, preferably 1to 2 substituents may be present on each ring. Examples of thesubstituents include a halogen, hydroxy, thiol, carboxy,methoxycarbonyl, hydroxymethyl, acetoxymethyl, cyano and acetylamino.Examples of the halogen are the same as those given for A_(D).Preferably, the ring is unsubstituted.

In the ketone derivatives of the present invention represented byformula [1D], X_(D) is preferably S, O or SO, most preferably S.

In Y_(D) in the ketone derivatives represented by general formula [1D],the straight or branched aliphatic hydrocarbon group having 1 to 6carbon atoms includes an alkyl or an alkenyl. Examples of the alkyl aremethyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl andtert-butyl. Examples of the alkenyl are vinyl, 2-propenyl, isopropenyland 2-butenyl. Preferably the aliphatic group is an alkyl having 1 to 4carbon atoms, more preferably ethyl. The aliphatic hydrocarbon group maybe unsubstituted or substituted. Where the aliphatic hydrocarbon groupis substituted, the group may contain, e.g., 1 to 6, preferably 1 to 4substituents. As such substituents, there are carboxy or a group derivedtherefrom, amino or a group derived therefrom and, hydroxy or a groupderived therefrom. The aromatic hydrocarbon ring or monocyclic aromaticheterocyclic ring having 3 to 6 carbon atoms refers to an aromatichydrocarbon ring such as a benzene ring and a aromatic heterocyclic ringsuch as a 5- or 6-membered ring containing nitrogen, oxygen or sulfur.Where the aromatic hydrocarbon ring or aromatic heterocyclic ring issubstituted, examples of such substituents are the same as those givenfor the aliphatic hydrocarbon group.

The group derived from carboxy includes a functional group of carboxy,such as an esterified or amidated carboxy group, cyano, hydroxymethyl oraminomethyl formed by reducing these functional groups, and functionalgroups derived therefrom by modification like acylation or alkylation ofthe functional groups. Preferably, the carboxy and the group derivedtherefrom include carboxy, COOR1 (wherein R1 is an unsubstituted orsubstituted alkyl or alkenyl having 1 to 4 carbon atoms), CONR2R3(wherein each of R2 and R3, which may be different or the same,independently represents hydrogen or a substituted or unsubstitutedalkyl having 1 to 4 carbon atoms) and COW (W is an unsubstituted orsubstituted heterocyclic ring). Herein, the alkyl shown by R1 in COOR1may be straight, branched or cyclic. Examples of the alkyl moiety aremethyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl,tert-butyl and cyclobutyl, preferably methyl, ethyl, and n-propyl, morepreferably methyl. Examples of the alkenyl are vinyl, 2-propenyl,isopropenyl and 2-butenyl. Where the alkyl or alkenyl is substituted,e.g., 1 to 6, preferably 1 to 3 substituents may be present. Examples ofthe substituents are a halogen, hydroxy, thiol, carboxy,methoxycarbonyl, acetyloxy, acetylthio, cyano and acetylamino. Examplesof the halogen are the same as defined for A. Preferably, the alkyl forR1 is unsubstituted.

Where the alkyl shown by R2 or R3 and its substituent(s) aresubstituted, examples of such substituents are the same as those definedfor R1.

Preferably W represents a saturated heterocyclic ring, more preferably,an azetidine, piperidine, pyrrolidine, piperazine or morpholine ring.These heterocyclic rings may be coupled to carbonyl via carbon ornitrogen, preferably to carbonyl via nitrogen. Where the heterocyclicring is substituted, 1 to 4, preferably 1 to 2 substituents may bepresent on each ring. Examples of the substituents are carboxy or agroup derived therefrom and amino or a group derived therefrom. Examplesof these substituents are as defined in the specification.

Examples of the group derived from amino include such functional groupsthat amino is alkylated, acylated, or sulfoylated nitro, hydroxyamino,imino and a heterocyclic group containing the nitrogen atom from theamino, preferably a group shown by NR4R5 (wherein each of R4 and R5,which may be different or the same, independently represents hydrogen,an unsubstituted or substituted alkyl having 1 to 4 carbon atoms or anunsubstituted or substituted acyl having 1 to 5 carbon atoms). In thegroup shown by NR4R5, the alkyl moiety for R4 and R5 and thesubstituents where the alkyl is substituted are the same as thosedefined for R1. The acyl for R4 and R5 may be straight, branched,cyclic, saturated or unsaturated. Representative examples of the acylare acetyl, propionyl, acroyl, propioloyl, n-butyryl, isobutyryl,crotonoyl, valeryl, isovaleryl and pivaloyl. Where the acyl issubstituted, examples of the substituents are the same as those definedfor R1. Preferably, the amino-derived group is NHCOR14 (wherein R14 isan alkyl having 1 to 4 carbon atoms in which hydrogen(s) may besubstituted with fluorine(s); examples of the alkyl are the same asthose given for R1). The number of fluorine atoms which may besubstituted is 1 to 9, preferably 1 to 7. Most preferably, R14 ismethyl.

Examples of the group derived from hydroxy include a functional group inwhich hydroxy is alkylated or acylated, a keto and a halogen, preferablyOCOR15 (wherein R15 is an alkyl having 1 to 4 carbon atoms and examplesof the alkyl are the same as those defined for R1).

Z_(D) in the ketone derivatives [1D] of the present invention representscarboxy or a group derived therefrom, an unsubstituted or substitutedalkyl or alkenyl having 1 to 4 carbon atoms, hydroxy or a group derivedtherefrom, amino or a group derived therefrom, sulfate or a groupderived therefrom, phosphate or a group derived therefrom, a monocyclicaromatic heterocyclic ring, a halogen or hydrogen. Examples of the groupderived from carboxy, amino or hydroxy are the same as defined above.Examples of the group derived from amino further include NHSO₂Ph,NHCOCF₃, NHCOC₂F₅, NHSO₂CF₃ and NHSO₂C₂F₅. Examples of the alkyl andalkenyl, and the substituents where the alkyl or alkenyl is substitutedare the same as those defined for A_(D). Examples of the group derivedfrom sulfate are groups from sulfonamide derivatives, e.g., SO₂NH₂,SO₂NHCH₃, SO₂N(CH₃)₂ and SO₂NHCOCH₃. Examples of the group derived fromphosphate are P(O)(OH)H, P(O)(OH)(NH₂) and P(O)(OH)CH(OCH₃)₂. Preferredexamples of Z_(D) include carboxy, COOR7 (wherein R7 is an unsubstitutedor substituted alkyl having 1 to 4 carbon atoms), CONR8R9 (wherein eachof R8 and R9, which may be different or the same, independentlyrepresents hydrogen or a substituted or unsubstituted alkyl having 1 to4 carbon atoms), cyano, hydroxy, CH₂OR10 (wherein R10 is hydrogen, anunsubstituted or substituted alkyl having 1 to 4 carbon atoms or anunsubstituted or substituted acyl having 1 to 5 carbon atoms), OCOR11(wherein R11 is an unsubstituted or substituted alkyl having 1 to 4carbon atoms), NR12R13 (wherein each of R12 and R13, which may be thesame or different, independently represents hydrogen, an unsubstitutedor substituted alkyl having 1 to 4 carbon atoms or an unsubstituted orsubstituted acyl having 1 to 5 carbon atoms), 5-tetrazolyl, a halogen orhydrogen. Examples of the alkyl moiety shown by R7, R8, R9, R10, R11,R12 and R13 and the substituents when the alkyl moiety is substitutedare the same as those defined for R1. Examples of the acyl shown by R10,R12 and R13 and the substituents when the acyl is substituted are thesame as those defined for R4. A preferred combination of R12 and R13 isthat R 12 is hydrogen and R13 is acetyl. Examples of the halogen arefluorine, chlorine, bromine and iodine, preferably fluorine andchlorine. More preferred examples of Z_(D) are carboxy, COOR7′ (whereinR7′ is an alkyl having 1 to 4 carbon atoms) and CH₂OR10′ (wherein R10′is hydrogen, an unsubstituted or substituted acyl having 1 to 5 carbonatoms). Examples of R7′ are the same as those given for R1. Examples ofthe acyl moiety in R10′ are the same as those given for R4, mostpreferably, carboxy, methoxycarbonyl, hydroxymethyl and acetyloxymethyl.

[E] Compound of formula [1E]

The compound of formula [1E] is represented by formula [1E] above.

[F] Compounds of formula [1F]

In the compounds of the present invention represented by general formula[1F], the unsubstituted or substituted aliphatic hydrocarbon grouphaving 1 to 4 carbon atoms, which is shown by A_(F), refers to an alkylor alkenyl having 1 to 4 carbon atoms which may optionally besubstituted. Examples of the alkyl group are methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl and tert-butyl. Examples of the alkenyl arevinyl, 2-propenyl, isopropenyl and 2-butenyl. Preferably, the aliphatichydrocarbon group is exemplified by methyl, ethyl, n-propyl andisopropyl, more preferably methyl. The aliphatic hydrocarbon group maybe unsubstituted or substituted. Where the aliphatic hydrocarbon groupis substituted, e.g., 1 to 6, preferably 1 to 3 substituents may bepresent. Examples of the substituents are an alkyl having 1 to 4 carbonatoms, a halogen, hydroxy, an alkyloxy having 1 to 4 carbon atoms,amino, a monoalkylamino or dialkylamino having 1 to 4 carbon atoms,nitro, cyano, trifluoromethyl, carboxy, an alkyloxycarbonyl having 1 to4 carbon atoms, an acyloxy having 1 to 5 carbon atoms, an acylthiohaving 1 to 5 carbon atoms and an acylamino having 1 to 5 carbon atoms.Examples of the halogen are bromine, chlorine and fluorine. Examples ofthe alkyl having 1 to 4 carbon atoms and the alkyl moiety with 1 to 4carbon atoms in the acyl having 1 to 5 carbon atoms are the same asthose defined for A_(F).

The unsubstituted or substituted aromatic hydrocarbon ring, aromaticheterocyclic ring or saturated heterocyclic ring group shown by A_(F) inthe compounds of general formula [1F] includes a benzene, 1-naphthalene,2-naphthalene, thiophene, furan, pyrrole, imidazole, oxazole, pyrazole,isoxazole, pyridine, pyrazine, indane, quinoline, isoquinoline,quinazoline, coumarine, pyrrolidine, piperidine or piperazine ring,preferably a benzene ring and a monocyclic aromatic heterocyclic ring,more preferably a benzene ring. These rings may be unsubstituted orsubstituted. Where the ring is substituted, e.g., 1 to 6, preferably 1to 3 substituents may be present on each ring. Examples of thesubstituents include an alkyl having 1 to 4 carbon atoms, a halogen,hydroxy, an alkyloxy having 1 to 4 carbon atoms, amino, a monoalkylaminoor dialkylamino having 1 to 4 carbon atoms, thiol, carboxy, analkyloxycarbonyl having 1 to 4 carbon atoms, an acyloxy having 1 to 5carbon atoms, an acylthio having 1 to 5 carbon atoms, an acylaminohaving 1 to 5 carbon atoms, cyano and trifluoromethyl. Examples of thehalogen are bromine, chlorine and fluorine. Examples of the alkyl having1 to 4 carbon atoms and the alkyl moiety in the acyl having 1 to 5carbon atoms are the same as those given for A. Preferred examples OfA_(F) are those unsubstituted, or those substituted with methyl,methoxy, methoxycarbonyl, nitro, cyano, a halogen or trifluoromethyl,for 1 to 3 hydrogen atoms.

In the compounds of general formula [1F], examples of the unsubstitutedor substituted aliphatic hydrocarbon group B_(F) having 1 to 4 carbonatoms are the same as those given for A_(F).

In the compounds of general formula [1F], A_(F) and B_(F) are combinedtogether to form an unsubstituted or substituted cycloalkan-1-one ringhaving 3 to 7 carbon atoms. Examples of the ring include acyclopropan-1-one, cyclobutan-1-one, cyclopentan-1-one, cyclohexan-1-oneand cycloheptan-1-one ring, preferably a cyclobutan-1-one,cyclopentan-1-one and cyclohexan-1-one ring, more preferablycyclopentan-1-one. These rings may be unsubstituted or substituted.Where the ring is substituted, e.g., 1 to 2 substituents may be presenton each ring. Examples of the substituents include a halogen, hydroxy,carboxy, methoxycarbonyl, acetoxy, acetylthio, cyano and acetylamino.Examples of the halogen are bromine, chlorine and fluorine. As anexample that there are the two substituents, a fused ring with anaromatic hydrocarbon ring or aromatic heterocyclic ring isrepresentative. Examples of the aromatic hydrocarbon ring formed byA_(F) and B_(F) are a benzene ring and a naphthalene ring. Examples ofthe aromatic heterocyclic ring are a 6-membered aromatic heterocyclicring such as a pyridine, pyrazine or pyrimidine ring, and a 5-memberedheteroaryl such as a thiophene, pyrrole, furan, oxazole, thiazole,isoxazole, isothiazole or azole ring. Preferably, the group formed byA_(F) and B_(F) is an aromatic hydrocarbon ring, more preferably abenzene ring. Where the ring is substituted, examples of thesubstituents are an alkyl having 1 to 4 carbon atoms, e.g., anunsubstituted alkyl such as ethyl, n-propyl and isopropyl, or an alkylsubstituted with a halogen (e.g., fluorine) such as trifluoromethyl; analkyloxy having 1 to 4 carbon atoms such as methoxy and ethoxy; nitro,and a halogen, e.g., fluorine, chlorine or bromine. Specific examplesare indan-1-one, 6,7-dihydro-5-oxocyclopenta[b]pyridine and5,6-dihydro-7-oxocyclopenta[b]pyridine, preferably indan-1-one.

In the compounds of the present invention represented by general formula[1F], the straight or branched aliphatic hydrocarbon group having 1 to10 carbon atoms, which is shown by X_(F) or Y_(F), refers to an alkyl oralkenyl having 1 to 10 carbon atoms. Preferably, the aliphatichydrocarbon group is an alkyl having 1 to 6 carbon atoms and examples ofthe alkyl group are ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl,isopropyl and isobutyl, more preferably ethyl, n-propyl and isopropyl,most preferably ethyl. The aliphatic group may be unsubstituted orsubstituted. Where the aliphatic group is substituted, the aliphaticgroup may contain, e.g., 1 to 6, preferably 1 to 3 substituents.Examples of the substituents are carboxy or a group derived therefrom,amino or a group derived therefrom and, hydroxy or a group derivedtherefrom.

The group derived from carboxy includes a functional group of carboxy,such as an esterified or amidated carboxy group (e.g., —COOR1, —COOR1′,—COOR1″, —CONR2R3, —CONR2′R3′, —CONR2″R3″, etc. described below), cyano,hydroxymethyl or aminomethyl formed by reducing these functional groups,and functional groups derived therefrom by modification like acylationof the functional groups (e.g., —CH₂OR4, —CH₂OR4′ described below).

Examples of the group derived from amino include such functional groupsthat amino is alkylated acylated or sulfonylated (e.g., —NR6R7 describedabove), nitro, hydroxyamino, imino and a heterocyclic group containingthe nitrogen atom from the amino.

Examples of the group derived from hydroxy include a functional group inwhich hydroxy is alkylated or acylated (e.g., —OR5 described above), aketo and a halogen.

In the compounds of the present invention represented by general formula[1F], examples of the heterocyclic group formed by linking X_(F) andY_(F) to each other directly or via a hetero atom are pyrrole,imidazole, indole, indazole, purine, carbazole, imidazolidine,imidazoline, pyrrolidine, piperidine, piperazine, morpholine andindoline ring. Preferably, the heterocyclic group is a monocyclicheterocyclic ring such as a pyrrole, imidazole, imidazolidine,imidazoline, pyrrolidine, piperidine, piperazine and morpholine ring,more preferably a saturated monocyclic heterocyclic ring such as apyrrolidine, piperidine and morpholine ring. These rings may beunsubstituted or substituted. Where the ring is substituted, e.g., 1 to6, preferably 1 to 3 substituents may be present on each ring. Examplesof the substituents include an alkyl having 1 to 4 carbon atoms, phenyl,carboxy or a group derived therefrom, amino or a group derived therefromand, hydroxy or a group derived therefrom. Examples of the group derivedfrom carboxy, amino or hydroxy are described above. Preferred examplesof the substituents are an alkyl having 1 to 4 carbon atoms and phenyl,more preferably methyl and phenyl. Preferred examples of the substitutedheteroaryl are imidazolidine and piperazine rings, more preferably a4-methylpiperazine and 4-phenylpiperazine ring.

In the compounds of the present invention represented by general formula[1F], Z_(F) is carboxy or a group derived therefrom, an unsubstituted orsubstituted alkyl or alkenyl having 1 to 4 carbon atoms, hydroxy or agroup derived therefrom, amino or a group derived therefrom, sulfate ora group derived therefrom, phosphate or a group derived therefrom, amonocyclic heteroaryl or a halogen. Examples of the group derived fromcarboxy, amino or hydroxy are described above. Examples of the groupderived from amino further include NHSO₂Ph, NHCOCF₃, NHCOC₂F₅, NHSO₂CF₃and NHSO₂C₂F₅. Examples of the group derived from sulfate are groupsfrom sulfonamide derivatives, e.g., SO₂NH₂, SO₂NHCH₃, SO₂N(CH₃)₂ andSO₂NHCOCH₃. Examples of the group derived from phosphate are P(O)(OH)H,P(O)(OH)(NH₂) and P(O)(OH)CH(OCH₃)₂. Examples of the alkyl group having1 to 4 carbon atoms are methyl, ethyl, n-propyl, isopropyl and n-butyl.Examples of the alkenyl having 1 to 4 carbon atoms are vinyl,2-propenyl, isopropenyl and 2-butenyl. Where the alkyl or alkenyl issubstituted, examples of such substituents are the same as those definedfor the aliphatic group in A_(F). Examples of the monocyclic heteroarylinclude 5-tetrazolyl, 3-(4H-5-oxo-1,2,4-oxadiazolyl),5-(3-hydroxyisoxazolyl), 5-(3-hydroxyisothiazolyl) and4-(3-hydroxy-1,2,5-thiadiazolyl). Examples of the halogen are fluorine,chlorine, bromine and iodine. More preferred examples of Z_(F) arecarboxy, COOR1 (wherein R1 is an unsubstituted or substituted alkylhaving 1 to 4 carbon atoms or phenyl), CONR2R3 (wherein each of R2 andR3, which may be different or the same, independently representshydrogen or a substituted or unsubstituted alkyl having 1 to 4 carbonatoms), cyano, CH₂OR4 (wherein R4 is hydrogen, an unsubstituted orsubstituted alkyl having 1 to 4 carbon atoms or an acyl having 1 to 5carbon atoms), —OR5 (wherein R5 is an unsubstituted or substituted alkylhaving 1 to 4 carbon atoms or an unsubstituted or substituted an acylhaving 1 to 5 carbon atoms), 5-tetrazolyl, chlorine and fluorine.Examples of the substituents for the alkyl or acyl are the same as thosedefined for the substituents of the aliphatic group shown by A_(F). Morepreferred examples of A_(F) are carboxy, COOR1′ (wherein R1′ is an alkylhaving 1 to 4 carbon atoms), CONR2′R3′ (wherein each of R2′ and R3′,which may be different or the same, independently represents hydrogen oran alkyl having 1 to 4 carbon atoms), cyano and CH₂OR4′ (wherein R4′ ishydrogen, an alkyl having 1 to 4 carbon atoms or an acyl having 1 to 5carbon atoms). Z_(F) as particularly preferred examples includescarboxy, COOR1″ (wherein R1″ is methyl or ethyl), CONR2″R3″ (whereineach of R2″ and R3″, which may be different or the same, independentlyrepresents hydrogen, methyl or ethyl) and cyano.

Representative examples of the compounds in accordance with the presentinvention are listed below.

Compounds of formula [1A]

(1A)trans-4-{(2R)-2-acetylamino-2-carboxyethylthio}methyl-3-oxo-1-cyclopentanecarboxylicacid;

(2A)trans-4-{(2R)-2-acetylamino-2-methoxycarbonylethylthio}methyl-3-oxo-1-cyclopentanecarboxylicacid;

(3A)2RS,4S)-2-{(2R)-2-acetylamino-2-carboxyethylthio}methyl-4-hydroxy-1-cyclopentanone;

(4A)2RS,4S)-2-[(2R)-3-acetylamino-3-{1-{(2S)-2-methoxycarbonyl}pyrrolidinyl]-3-oxypropylthio}methyl-4-hydroxy-1-cyclopentanone;

(5A)2-{(2R)-2-acetylamino-2-carboxyethylthio}methyl-3-oxo-1-indanecarboxylicacid;

(6A)2-{(2R)-2-acetylamino-2-methoxycarbonylethylthio}methyl-3-oxo-1-indanecarboxylicacid

Compounds of formula [1B]

(1B)(1R,2S)-2-[(2R)-{2-acetylamino-3-oxo-3-(1-pyrrolidinyl)}propylthio]methyl-3-oxo-1-cyclopentanecarboxylicacid;

(2B)(1R,2S)-2-[(2R)-{2-acetylamino-3-(4-morpholinyl)-3-oxo}propylthio]methyl-3-oxo-1-cyclopentanecarboxylicacid;

(3B)(1R,2S)-2-[(2R)-{2-acetylamino-3-oxo-3-(1-piperidinyl)propylthio}]methyl-3-oxo-1-cyclopentanecarboxylicacid;

(4B)(1R,2S)-2-[(2R)-({2-carboxy-2-pentafluoropropionylamino)ethylthio]methyl-3-oxo-1-cyclopentanecarboxylicacid;

(5B)trans-2-[(2R)-{2-acetylamino-3-oxo-3-(1-pyrrolidinyl)}propylthio]methyl-3-methoxycarbonyl-1-cyclopentanone;

(6B)trans-2-[(2R)-[2-acetylamino-3-{1-((2S)-2-methoxycarbonylpyrrolidinyl)}-3-oxo]propylthio]methyl-3-oxo-1-cyclopentanecarboxylicacid;

(7B)trans-2-[(2R)-[2-acetylamino-3-{1-((2S)-2-methoxycarbonylazetidinyl)}-3-oxo]propylthio]methyl-3-oxo-1-cyclopentanecarboxylicacid;

(8B)trans-2-[(2R)-(2-carboxy-2-pentafluoropropionylamino)ethylthio]methyl-3-hydroxymethyl-1-cyclopentanone;

(9B)trans-2-[(11-acetylamino-11-carboxy)undecylthio]methyl-3-oxo-1-cyclopentanecarboxylicacid;

(10B)(1R,2S)-2-[(2R)-{2-acetylamino-3-oxo-3-(1-piperazinyl)propylthio}]methyl-3-oxo-1-cyclopentanecarboxylicacid;

(11B)(1R,2S)-2-[(2R)-{2-acetylamino-3-oxo-3-(1-(4-hydroxymethyl)piperazinyl)propylthio}]methyl-3-oxo-1-cyclopentanecarboxylicacid;

(12B)(1R,2S)-2-[(2R)-{2-acetylamino-3-oxo-3-(1-(4-tert-butoxycarbonyl)piperazinyl)propylthio}]methyl-3-oxo-1-cyclopentanecarboxylicacid;

(13B)(1R,2S)-2-[(2R)-[2-acetylamino-3-oxo-3-{1-(4-phenyl)piperazinyl}propylthio]methyl-3-oxo-1-cyclopentanecarboxylicacid;

(14B)(1R,2S)-2-{3-(3-pyridyl)propylthio}methyl-3-oxo-1-cyclopentanecarboxylicacid;

(15B) (1R,2S)-2-[3-{3-(1-methylpyridiniumiodide)}propylthio]methyl-3-oxo-1-cyclopentanecarboxylic acid;

(16B)(1R,2S)-2-[2-acetylamino-2-(5-tetrazolyl)ethylthio]]methyl-3-oxo-1-cyclopentanecarboxylicacid

Compounds of formula [1C]

(1C)5-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-2-cyclopenten-1-one;

(2C)(4R)-2-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-hydroxy-2-cyclopenten-1-one;

(3C)2-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-3-hydroxy-2-cyclopenten-1-one;

(4C)5-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-carboxy-2-cyclopenten-1-one;

(5C)5-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-methoxycarbonyl-2-cyclopenten-1-one;

(6C)5-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-hydroxymethyl-2-cyclopenten-1-one;

(7C)5-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-acetoxymethyl-2-cyclopenten-1-one;

(8C)5-[(2R)-(2-acetylamino-2-methoxycarbonyl)ethylthio]methyl-4-carboxy-2-cyclopenten-1-one;

(9C) 5-[(2-acetylamino)ethylthio]methyl-4-carboxy-2-cyclopenten-1-one;

(10C)2-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-3-carboxy-2-cyclopenten-1-one;

(11C)2-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-3-methoxycarbonyl-2-cyclopenten-1-one;

(12C)2-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-3-hydroxymethyl-2-cyclopenten-1-one;

(13C)2-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-3-acetoxymethyl-2-cyclopenten-1-one;

(14C)2-[(2R)-(2-acetylamino-2-methoxycarbonyl)ethylthio]methyl-3-carboxy-2-cyclopenten-1-one;

(15C)2-[(2-methoxycarbonyl)ethylthio]methyl-3-carboxy-2-cyclopenten-1-one;

(16C) 2-[(2-acetylamino)ethylthio]methyl-3-carboxy-2-cyclopenten-1-one

Compounds of formula [1D]

(1D) 3-{(2R)-2-acetylamino-2-carboxyethylthio}methyl-4-oxo-1-n-pentanoicacid;

(2D)3-{(2R)-2-acetylamino-2-methoxycarbonylethylthio}methyl-4-oxo-1-n-pentanoicacid;

(3D)trans-2-{(2R)-2-acetylamino-2-methoxycarbonylethylthio}methyl-3-ethoxycarbonyl-1-cyclobutanone;

(4D)trans-2-{(2R)-2-acetylamino-2-carboxyethylthio}methyl-3-oxo-1-cyclobutanecarboxylicacid;

(5D)2-(2,3-dihydroxy-n-propyl)thiomethyl-3-acetoxymethyl-1-cyclobutanone;

(6D)2-{(2R)-2-acetylamino-2-carboxyethylthio}methyl-3-oxo-1-cyclohexanecarboxylicacid;

(7D)3-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-oxo-4-phenylbutyricacid;

(8D)3-[(2R)-(2-acetylamino-2-methoxycarbonyl)ethylthio]methyl-4-oxo-4-phenylbutyricacid;

(9D)3-[(2R)-(2-acetylamino-2-methoxycarbonyl)ethylthio]methyl-4-(4-methoxyphenyl)-4-oxobutyricacid;

(10D)3-{2-(acetylamino)ethylthio}methyl-4-(4-methoxyphenyl)-4-oxobutyricacid;

(11D) 3-{2-(acetylamino)ethylthio}methyl-4-oxo-4-phenylbutyric acid;

(12D) 3-{2-(acetylamino)ethylthio}methyl-4-(4-methylphenyl)-3-oxobutyricacid;

(13D)3-{(2R)-(2-acetylamino-2-methoxycarbonyl)ethylthio}methyl-4-(4-methylphenyl)-3-oxobutyricacid;

(14D)3-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-oxo-4-(4-trifluoromethylphenyl)butyricacid;

(15D)3-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-oxo-4-(2-trifluoromethylphenyl)butyricacid;

(16D)3-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-oxo-4-(3-trifluoromethylphenyl)butyricacid;

(17D)3-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-oxo-4-(3-pyridyl)butyricacid;

(18D)3-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-oxo-4-(2-pyridyl)butyricacid;

(19D)3-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-oxo-4-(4-pyridyl)butyricacid;

(20D)3-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-(1-naphthyl)-4-oxobutyricacid;

(21D)3-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-(2-naphthyl)-4-oxobutyricacid;

(22D)3-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-oxo-4-(1-piperidyl)butyricacid;

(23D)3-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-(4-methyl-1-piperazinyl)-4-oxobutyricacid;

(24D)3-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-oxo-4-(4-phenyl-1-piperazinyl)butyricacid;

(25D)3-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-(2-furyl)-4-oxobutyricacid;

(26D)3-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-(3-furyl)-4-oxobutyricacid;

(27D)3-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-oxo-4-(2-thienyl)butyricacid;

(28D)3-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-oxo-4-(3-thienyl)butyricacid;

(29D)3-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-oxo-4-(2-pyrrolyl)butyricacid;

(30D)3-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-oxo-4-(3-pyrrolyl)butyricacid;

(31D)3-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-(2-imidazolyl)-4-oxobutyricacid;

(32D)3-[(2R)-(2-acetylamino-2-methoxycarbonyl)ethylthio]methyl-4-oxo-4-(3-pyridyl)butyricacid;

(38D)4-[(2R)-{(2-acetylamino-2-carboxy)ethylthio}]methyl-5-oxo-5-phenylpentanoicacid

Compound of formula [1E]

(1E) (1R,2S)-2-[N-(panthoyl--alanylamido)ethylthio]methyl-3-oxo-1-cyclopentanecarboxylic acid

Compounds of formula [1F]

(1F) 4-oxo-4-phenyl-3-(1-piperidyl)methylbutyric acid;

(2F) 4-(4-methylphenyl)-4-oxo-3-(1-piperidyl)methylbutyric acid;

(3F) 4-(4-methoxyphenyl)-4-oxo-3-(1-piperidyl)methylbutyric acid;

(4F) 4-oxo-4-phenyl-3-(1-pyrrolidinyl)methylbutyric acid;

(5F) 3-(4-morpholinyl)methyl-4-oxo-4-phenylbutyric acid;

(6F) 3-{1-(4-methylpiperazinyl)}methyl-4-oxo-4-phenylbutyric acid;

(7F) 3-(diethylamino)methyl-4-oxo-4-phenylbutyric acid;

(8F) (1R,2R)-3-oxo-2-(1-piperidyl)methyl-1-cyclopentanecarboxylic acid;

(9F) 4-oxo-3-(1-piperidyl)methyl-4-(4-trifluoromethylphenyl) butyricacid;

(10F) 4-oxo-3-(1-piperidyl)methyl-4-(2-trifluoromethylphenyl) butyricacid;

(11F) 4-oxo-3-(1-piperidyl)methyl-4-(3-trifluoromethylphenyl)butyricacid;

(12F) 4-oxo-3-(1-piperidyl)methyl-4-(3-pyridyl)butyric acid;

(13F) 4-oxo-3-(1-piperidyl)methyl-4-(2-pyridyl)butyric acid;

(14F) 4-oxo-3-(1-piperidyl)methyl-4-(4-pyridyl)butyric acid;

(15F) 3-oxo-2-(1-piperidyl)methyl-1-indanecarboxylic acid;

(16F) 3-oxo-2-(1-pyrrolidinyl)methyl-1-indanecarboxylic acid;

(17F) 2-(4-morpholinyl)methyl-3-oxo-1-indanecarboxylic acid;

(18F) 2-{1-(4-methylpiperazinyl)}methyl-3-oxo-1-indanecarboxylic acid;

(19F) 3-{1-(4-phenylpiperazinyl)}methyl-4-oxo-4-phenylbutyric acid;

(20F) 4-oxo-4-(1-naphthyl)-3-(1-piperidyl)methylbutyric acid;

(21F) 4-oxo-4-(2-naphthyl)-3-(1-piperidyl)methylbutyric acid

(22F) 4-oxo-4-(1-piperidyl)-3-(1-piperidyl)methylbutyric acid;

(23F) 4-oxo-4-(4-methyl-1-piperazinyl)-3-(1-piperidyl)methylbutyricacid;

(24F) 4-oxo-4-(4-phenyl-1-piperazinyl)-3-(1-piperidyl)methylbutyricacid;

(25F) 4-oxo-4-(1-naphthyl)-3-(1-pyrrolidinyl)methylbutyric acid;

(26F) 4-oxo-4-(2-naphthyl)-3-(1-pyrrolidinyl)methylbutyric acid;

(26F) 4-(2-furyl)-4-oxo-3-(1-piperidyl)methylbutyric acid;

(27F) 4-(3-furyl)-4-oxo-3-(1-piperidyl)methylbutyric acid;

(28F) 4-oxo-3-(1-piperidyl)methyl-4-(2-thienyl)butyric acid;

(29F) 4-oxo-3-(1-piperidyl)methyl-4-(3-thienyl)butyric acid;

(30F) 4-oxo-3-(1-piperidyl)methyl-4-(2-pyrrolyl)butyric acid;

(31F) 4-oxo-3-(1-piperidyl)methyl-4-(3-pyrrolyl)butyric acid;

(32F) 4-(2-imidazolyl)-4-oxo-3-(1-piperidyl)methylbutyric acid;

(33F) 4-oxo-4-phenyl-3-(1-piperidyl)methylbutyronitrile;

(34F) methyl 4-oxo-4-phenyl-3-(1-piperidyl)methylbutyrate;

(35F) ethyl 4-oxo-4-phenyl-3-(1-piperidyl)methylbutyrate;

(36F) 4-(2-imidazolyl)-4-oxo-3-(1-pyrrolidinyl)methylbutyric acid;

(37F) 4-oxo-4-phenyl-3-(1-pyrrolidinyl)methylbutyronitrile;

(38F) 4-oxo-4-phenyl-3-(4-methyl-1-piperazinyl)methylbutyronitrile;

(39F) 4-oxo-4-phenyl-3-(4-morpholinyl)methylbutyronitrile;

(40F) 4-(2-imidazolyl)-4-oxo-3-(4-morpholinyl)methylbutyric acid;

(41F) 2-methyl-4-oxo-4-phenyl-3-(1-piperazinyl)methylbutyric acid;

(42F) 4-(1-piperazinyl)methyl-5-oxo-5-phenylpentanoic acid

The compounds of the present invention may also be present in the formof stereoisomers such as geometrical isomers and mixtures thereof,diastereoisomers and mixtures thereof, optical isomers and racemicisomers. The compounds of the present invention cover all of thesestereoisomers and mixtures thereof.

The compounds of the present invention may optionally be present in theform of pharmacologically acceptable salts thereof. Examples of suchsalts are salts with acids including inorganic salts such ashydrochlorides, sulfates, phosphates, and Group IIIA salts, e.g.,aluminum salts, etc.; and organic salts such as p-toluenesulfonates. Assalts with bases, there are salts with alkali metals such as sodium orpotassium, salts with alkaline earth metals such as calcium, and organicsalts with methylamine, ethylenediamine, etc. These pharmacologicallyacceptable salts of the compounds of the present invention may beprepared by known methods.

Hereinafter representative processes for preparing the compounds of thepresent invention are shown below but are not deemed to be limited tothese processes only. The compounds of the present invention shown belowand intermediates thereof may be isolated by conventional means ofextraction, recrystallization, chromatography and the like.

[A] Processes for producing the compounds of formula [1A]

The compounds of general formula [1A] wherein X_(A) is S, O, or NH areprepared by reacting cyclopentanone derivatives (the carbonyl at the1-position thereof may be protected if necessary; hereinafter simplyreferred to as reactive derivatives) represented by general formula[2A]:

(wherein U is a leaving group and, Z1′_(A), Z2′_(A) and Z3′_(A) have thesame significance as defined in Z1_(A), Z2_(A) and Z3A but when thesegroups contain a functional group(s), these groups may optionally beprotected), with compounds of general formula [3A]:

HX_(A)2−Y′_(A)  [3A]

(wherein X_(A)2 is S, O or NH and Y′_(A) has the same significance asdefined for Y_(A) but where it contains a functional group, thefunctional group may be protected, if desired), and when required,removing the protective group. Preferred examples of the reactivederivatives described above are compounds of general formulas [4A],[5A], [6A], [7A] and [8A].

In the formulas above, R15 is an hydrocarbon group having 1 to 10 carbonatoms, such as an alkyl, an alkenyl or an aryl. These groups may besubstituted or unsubstituted. Where a substituent(s) are a functionalgroup(s), the functional groups may be protected with protective groups,if necessary and desired. Each of R16 and R17, which may be the same ordifferent, independently represents an alkyl having 1 to 4 carbon atoms,or R16 and R17 are combined together to form a piperazine or pyrrolidinering. Z1′_(A), Z2′_(A) and Z3′_(A) have the same significance as definedabove.

Examples of the compounds of general formulas [4A], [5A], [6A] and [7A]are illustrated below.

(a)4-[(2,3-O-isopropylidene)propylsulfonyl]methyl-3-oxo-1-cyclopentanecarboxylicacid

(b) 4-methylidene-3-oxo-1-cyclopentanecarboxylic acid

(c) (2RS,4S)-2-{(2R)-(2-acetylamino-2-methoxycarbonyl)ethylsulfonyl}methyl-4-hydroxycyclopentan-1-one

In general formula [3A] wherein X_(A) is S and Y_(A) is an amino acidderivative residue, the compounds of formula [3A] include the following:

(d) (2R)-2-acetylamino-2-carboxyethanethiol

(e) (2R)-2-acetylamino-2-methoxycarbonylethanethiol

For this reaction, any condensation process may be used so long as thecompounds of formula [2A] can be condensed with the compounds of formula[3A]. The reaction is carried out generally in an organic solvent, wateror a mixture thereof. As the organic solvent there may be employed anaromatic hydrocarbon such as benzene, toluene, etc.; an alcohol such asmethanol, ethanol, etc.; an ether such as tetrahydrofuran, diethylether, etc.; a halogenated hydrocarbon such as methylene chloride,chloroform, etc.; a ketone such as acetone, methyl ethyl ketone, etc.;an aprotic polar solvent such as dimethyl sulfoxide, dimethylformamide,etc. Preferred examples of the solvent are an ether such astetrahydrofuran or diethyl ether, a halogenated hydrocarbon such asmethylene chloride or chloroform, a ketone such as acetone or methylethyl ketone, an aprotic polar solvent such as dimethyl sulfoxide ordimethylformamide, or a mixture of such solvent and water. The reactionproceeds generally in the presence of an acid or a base or in theabsence or any catalyst, preferably under basic conditions usinginorganic bases, e.g., potassium hydroxide, sodium hydroxide, potassiumcarbonate, sodium carbonate, sodium hydride, etc., or organic bases suchas triethylamine, 1,8-diazabicyclo[5.4.0]-undeca-7-ene, etc. Thesereactants are employed in an amount of approximately 0.1 to 20-foldmols, preferably approximately 0.5 to 5-fold mols. The reactiontemperature is not particularly limited so that the reaction may becarried out under cooling, at ambient temperature or with heating.Preferably, the reaction is performed at a temperature between 0° C. and100° C. The compounds of formula [2A] may be reacted with the compoundsof formula [3A] in an equimolar amount. Practically, the compounds offormula [3A] may be used in an excess amount, e.g., 1 to 2-fold mols.The reaction is performed in 0.1 to 200 hours, preferably 0.1 to 72hours.

The compounds of formula [1A] wherein X_(A) is SO₂ can be prepared byoxidizing the compounds of formula [1A] wherein X_(A) is S, with anoxidizing agent. As the oxidizing agent, an organic peracid such asm-chloroperbenzoic acid, etc., an inorganic oxidizing agent such aspermanganate, chromic acid, ruthenium tetroxide, etc., hydrogenperoxide, an organic peroxide, etc., preferably an organic peracid suchas m-chloroperbenzoic acid.

The compounds of formula [1A] wherein X_(A) is SO can be prepared byoxidizing the compounds of formula [1A] wherein X_(A) is S, with anoxidizing agent. As the oxidizing agent, an organic peracid such asm-chloroperbenzoic acid, etc., an inorganic oxidizing agent such asmanganese dioxide, chromic acid, ruthenium tetroxide, etc., hydrogenperoxide, an organic peroxide, a halogen type oxidizing agent such asperiodic acid, etc.

For example, Compounds (a) and (b) described above are prepared by thefollowing procedure.

Starting 2,4-bis(methoxycarbonyl)cyclopentanone (Compound 1A-A) is knownand can be prepared as a mixture of2,3-bis(methoxycarbonyl)cyclopentanone (Compound 1A-a) by the processdescribed in, e.g., J. Org. Chem., 47, 2379 (1982) or by a modificationthereof. After the keto group of the mixture (Compound 1A-B and Compound1A-b) is protected, the ester is converted into hydroxymethyl byreduction. The protective group is then removed to give2,4-bis(hydroxymethyl)cyclopentanone (Compound 1A-C) and2,3-bis(hydroxymethyl)cyclopentanone (Compound 1A-c). Compound (1A-c) isremoved by silica gel column chromatography to isolate Compound (1A-C).Compound (1A-C) is acetylated in a conventional manner to give Compound(1A-D). The reaction for preparing Compound (1A-E) from Compound (1A-D)is carried out under similar conditions as used for the condensationbetween the compounds of formula [2A] and the compounds of formula [3A].In this case, alpha-thioglycerine is used as the compound of formula[3A]. Next, the 1,2-diol moiety in Compound (1A-E) is protected. As theprotective group, an acetal, a ketal or an ortho-ester may be employed.Compound (1A-E) is then converted into the isopropylidene preferably inthe presence of an acid catalyst and acetone or its activatedderivatives to give Compound (1A-F). Subsequently, Compound (1A-F) issubjected to alkaline hydrolysis in a conventional manner to remove theacetyl and give Compound (1A-G). Next, Sulfide of Compound (1A-G) isoxidized form to sulfone. Thus, Compound (1A-H) is obtained. Thereaction is carried out under conditions similar to those used for theforegoing oxidation wherein the conditions are set forth so as not tooxidize the hydroxy. In the case that the hydroxy is also oxidized,Compound (a) is obtained. Next, the hydroxy is oxidized to give Compound(a). Examples of the oxidizing agent that can be used are inorganicoxidizing agents such as permanganates and chromic acid, preferablychromic acid. Compound (b) may be prepared by maintaining Compound (a)under basic conditions similar to the conditions used for thecondensation between the compounds of formula [2A] and the compounds offormula [3A]. In this reaction, there is no need to add the compounds offormula [3A]. Reactants used for the reaction are inorganic bases, e.g.,potassium hydroxide, sodium hydroxide, potassium carbonate, sodiumcarbonate, etc., or organic bases such as triethylamine,1,8-diazabicyclo[5.4.0]-undeca-7-ene, etc., preferably an organic basesuch as triethylamine.

Compound (c) can be prepared by the following procedure.

Starting(4R)-2-(N,N-diethylamino)methyl-4-tert-butyldimethylsiloxy-2-cyclopenten-1-one(Compound 3A-a) is known and commercially available (from, e.g., TheShin-Etsu Chemical Co., Ltd.). For the reaction for preparing Compound(3A-b) from Compound (3A-a), reaction conditions similar to those usedfor the condensation between the compounds of formula [2A] and formula[3A] may be used. In this reaction, N-acetyl-L-cysteine is employed asthe compound of formula [3B]. The protective group for the hydroxy ofCompound (3B-b) is removed in a conventional manner, using an acid or afluorine compound. By oxidation, the sulfide of Compound (3B-c) is thenconverted into the corresponding sulfone to give Compound (3B-d). Thereaction can be performed under conditions similar to those for theoxidation above, so as not to oxidize the hydroxy. The double bond inthe ring is then reduced with a reducing agent to give Compound (c). Asthe reducing agent there may be employed a catalytic reducing agent suchas palladium-carbon, etc., a soluble metal reducing agent such aslithium-ammonia, etc., an organic tin hydride compound, an organicsilicon hydride compound, etc., preferably a catalytic reducing agentsuch as palladium-carbon.

The compounds of general formulas [4A] through [7A] other than Compounds(a) to (c) described above may be prepared by appropriately modifyingthe foregoing processes used to prepare Compounds (a) to (c).

Compound (c) is commercially available (from, e.g., Tokyo Kasei K.K.).Compound (e) is readily prepared by heating Compound (d) in methanol inthe presence of an acidic catalyst. As the acidic catalyst, there are anorganic acid such as hydrochloric acid, sulfuric acid, etc., an organicacid such as p-toluenesulfonic acid, or a Lewis acid such as boronfluoride etherate, etc., preferably an organic acid such asp-toluenesulfonic acid.

For example, Compound (4A) of the present invention can be readilyprepared by amidation of Compound (3A) as shown below.

The amidation is effected by condensation under basic conditions orusing a condensing agent. The use of a condensing agent is preferablefor the amidation. Examples of the condensing agent aredicyclocarbodiimide (DCC) and WSC.

Compounds (5A) and (6A) of the present invention can be prepared byreacting the compounds of general formula [8a] with the compounds ofgeneral formula [3A] while heating. The reaction is carried out in theabsence of a solvent or in an organic solvent with heating to 30° C. to200° C. to give the desired product. As the compounds of formula (8A],e.g., (f) 2-(1-piperidylmethyl)-3-oxo-1-indanecarboxylic acid isrepresentative. Compound (f) may be prepared by a modification of theprocess described in J. Med. Chem., 7, 716 (1964).

[B] Processes for preparing the compounds of formula 1B]

The compounds of general formula [1B] wherein X_(B) is S, O or NH areprepared by reacting 2,3-substituted cyclopentanone derivatives (thecarbonyl at the 1-position may be suitably protected; hereinafter simplyreferred to as reactive derivatives) represented by general formula[2B]:

(wherein U is a leaving group and, Z′_(B) has the same significance asthat of Z_(B) but when the group contains a functional group, thefunctional group may be protected suitably), with compounds of generalformula [3B]:

HX_(B)2−Y′_(B)  [3B]

(wherein X_(B)2 is S, O or NH and Y′_(B) has the same significance asdefined for Y_(B) but where it contains a functional group, thefunctional group may be protected suitably), and when required, removingthe protective group. Preferred examples of the reactive derivativesdescribed above are compounds of general formulas [4B], [5B], [6B] and[7B].

In the formulas above, R18 is an aliphatic group having 1 to 10 carbonatoms, such as an alkyl, an alkenyl or an aryl. These groups may besubstituted or unsubstituted. Where a functional group(s) are containedas a substituent(s), the functional groups may be adequately protectedwith protective groups.

Examples of the compounds of general formulas (4B], [5B], [6B] and [7B]are given below.

(a) 2,3-bis(acetoxymethyl)cyclopentanone

(b) 3-acetoxymethyl-2-methylidenecyclopentanone

(c)2-[(2,3-O-isopropylidene)propylsulfonyl]methyl-3-oxo-1-cyclopentanecarboxylicacid

(d)2-[(2,3-O-isopropylidene)propylsulfonyl]methyl-3-methoxycarbonylcyclopentanone

(e) 2-methylidene-3-oxo-1-cyclopentanecarboxylic acid

(f) 3-methoxycarbonyl-2-methylidenecyclopentanone

In the general formula [3B] wherein X_(B) is S and Y_(B) is an aminoacid derivative residue, the compounds of formula [3B] include thefollowing:

(g) (2R)-2-acetylamino-3-oxo-3-(1-pyrrolidinyl)propanethiol

(h) (2R)-2-acetylamino-3-(4-morpholinyl)-3-oxopropanethiol

(i) (2R)-2-acetylamino-3-oxo-3-(1-piperidyl)propanethiol

(j) (2R)-2-acetylamino-3-oxo-3-(1-pyrrolidinyl)propanethiol

(k)(2R)-2-acetylamino-3-[1-{(2S)-2-methoxycarbonyl}pyrrolidinyl)-3-oxopropanethiol

(l)(2R)-2-acetylamino-3-[1-{(2S)-2-methoxycarbonyl}azetidinyl)-3-oxopropanethiol

(m) (2R)-2-acetylamino-3-oxo-3-(1-piperazinyl)propanethiol

(n)(2R)-2-acetylamino-3-{1-(4-hydroxymethyl)piperazinyl}-3-oxopropanethiol

(o)(2R)-2-acetylamino-3-{1-(4-tert-butoxycarbonyl}piperazinyl)-3-oxopropanethiol

(p) (2R)-2-acetylamino-3-{1-(4-phenyl)piperazinyl}-3-oxopropanethiol

(q) (2R)-2-carboxy-2-pentafluoropropionylaminoethanethiol

(r) 1-acetylamino-1-carboxy-11-mercaptoundecanethiol

(s) 2-acetylamino-2-(5-tetrazolyl)ethanethiol

(t) 3-(3-pyridyl)propanethiol

(u) 3-{3-(1-methylpyridinium iodide)}propanethiol

The above reaction may be effected through any condensation so long asthe compounds of formula [2B] can be condensed with the compounds offormula [3B]. The reaction is carried out generally in an organicsolvent, water or a mixture thereof. As the organic solvent there may beemployed an aromatic hydrocarbon such as benzene, toluene, etc.; analcohol such as methanol, ethanol, etc.; an ether such astetrahydrofuran, diethyl ether, etc.; a halogenated hydrocarbon such asmethylene chloride, chloroform, etc.; a ketone such as acetone, methylethyl ketone, etc.; an aprotic polar solvent such as dimethyl sulfoxide,dimethylformamide, etc. Preferred examples of the solvent are an ethersuch as tetrahydrofuran or diethyl ether, a halogenated hydrocarbon suchas methylene chloride or chloroform, a ketone such as acetone or methylethyl ketone, an aprotic polar solvent such as dimethyl sulfoxide ordimethylformamide, or a mixture of such solvent and water. The reactionproceeds generally in the presence of an acid or a base or in theabsence or a catalyst, preferably under basic conditions. Reactants usedfor the reaction are inorganic bases, e.g., potassium hydroxide, sodiumhydroxide, potassium carbonate, sodium carbonate, sodium hydride, etc.,or organic bases such as triethylamine,1,8-diazabicyclo[5.4.0]-undeca-7-ene, etc. These reactants are employedin an amount of approximately 0.1 to 20-fold mols, preferablyapproximately 0.5 to 5-fold mols. The reaction temperature is notparticularly limited so that the reaction may be carried out undercooling, at ambient temperature or with heating. Preferably, thereaction is performed at a temperature between 0° C. and 100° C. Thecompounds of formula [2B] may be reacted with the compounds of formula[3B] in an equimolar amount. Practically, the compounds of formula [3B]may be used in an excess amount, e.g., 1 to 2-fold mols. The reaction isperformed in 0.1 to 200 hours, preferably 0.1 to 72 hours.

The compounds of formula [1B] wherein X_(B) is SO₂ can be prepared byoxidizing the compounds of formula [1B] wherein X_(B) is S, with anoxidizing agent. As the oxidizing agent, an organic peracid such asm-chloroperbenzoic acid, etc., an inorganic oxidizing agent such aspermanganate, chromic acid, ruthenium tetroxide, etc., hydrogenperoxide, an organic peroxide, etc., preferably an organic peracid suchas m-chloroperbenzoic acid.

The compounds of formula [1B] wherein X_(B) is SO can be prepared byoxidizing the compounds of formula [1B] wherein X_(B) is S, with anoxidizing agent. As the oxidizing agent, an organic peracid such asm-chloroperbenzoic acid, etc., an inorganic oxidizing agent such asmanganese dioxide, chromic acid, ruthenium tetroxide, etc., hydrogenperoxide, an organic peroxide, a halogen type oxidizing agent such asperiodic acid, etc.

For example, Compounds (a) and (b) described above are prepared by thefollowing procedure.

Starting 2,3-bis(hydroxymethyl)cyclopentanone (Compound a-1) is known byliterature and may be prepared, e.g., by the method described inJapanese Patent KOKAI No. Hei 5-1044 or a modification thereof. Compound(a-1) is acetylated in a conventional manner to give Compound (a).Compound (a) that is optically active and has a steric configuration of(2R,3R) may be obtained according to the process disclosed in JapanesePatent KOKAI No. Hei 8-231469. The optically active form of Compound (a)may also be prepared, e.g., by optical resolution of the opticallyinactive form by chromatography for optical resolution. Compound (b) maybe prepared by maintaining Compound (a) under basic conditions similarto the conditions used for the condensation between the compounds offormula [2B] and the compounds of formula [3B]; in conducting thisreaction, there is no need to use the compounds of formula [3B].Reactants used for the reaction are inorganic bases, e.g., potassiumhydroxide, sodium hydroxide, potassium carbonate, sodium carbonate,sodium hydride, etc., or organic bases such as triethylamine,1,8-diazabicyclo[5.4.0]-undeca-7-ene, etc., preferably an organic basesuch as triethylamine.

Compound s (c) and (d) may be prepared as indicated below.

The reaction for preparing Compound (a-2) from Compound (a) is carriedout under similar conditions as used for the condensation between thecompounds of formula [2B] and the compounds of formula [3B]. In thiscase, alpha-thioglycerine is used as the compound of formula [3B]. Next,the 1,2-diol moiety in Compound (a-2) is protected. As the protectivegroup, an acetal, a ketal or an ortho-ester may be employed. Compound(a-2) is then converted into the isopropylidene preferably in thepresence of an acid catalyst and acetone or its activated derivatives togive Compound (a-3). Subsequently, Compound (a-3) is subjected toalkaline hydrolysis in a conventional manner to remove the acetyl. Thus,Compound (a-4) is obtained. Next, the sulfide of Compound (a-4) isoxidized to the sulfone to prepare Compound (a-5). The reaction iscarried out under conditions similar to those used for the oxidationdescribed above, wherein the conditions are set forth so as not tooxidize the hydroxy. In the case that the hydroxy is also oxidized,Compound (a) is obtained. The hydroxy is then oxidized to give Compound(c). Examples of the oxidizing agent that can be used in the reactionare an inorganic oxidizing agents such as permanganates and chromicacid, preferably chromic acid. Finally, the carboxylic acid in Compound(c) is esterified in a conventional manner to prepare Compound (d).

Compounds (e) and (f) can be prepared from Compounds (c) and (d) underconditions similar to the conditions used to convert Compound (a) toCompound (b).

Optically active form (Compounds C and D) of Compounds (c) and (d) maybe prepared in a similar manner to the process for preparing Compounds(c) and (d) described above, which is illustrated below.

The compounds of general formulas [4B] through [7B] other than Compounds(a) to (f) described above may be prepared by appropriately modifyingthe foregoing processes used to prepare Compounds (a) to (f).

Compounds (g) to (u) may be prepared as shown below.

N-acetyl-L-cysteine (g-1) is benzoylated in a conventional manner toprepare Compound (g-2). Then, compounds of general formula [8b] below:

HW4  [8B]

wherein W4 is 1-piperidyl, 1-pyrrolidinyl, 4-morpholinyl,1-(2-methoxycarbonyl)azetidinyl, 1-(2-methoxycarbonyl)pyrrolidinyl,1-piperazinyl, 1-(4-hydroxyethyl)piperazinyl, 4-phenylpiperazinyl or1-(4-tert-butoxycarbonyl)piperazinyl, are subjected to an amide-formingreaction in a conventional manner. Thus, Compound (g-3) is prepared. Theprotective benzoyl is removed by hydrolysis to give Compounds (g) to(p).

Compound (q) can be readily prepared by reacting L-cysteine withpentafluoropropionic anhydride.

Compound (r) can be prepared as shown below.

Compound (r-2) can be prepared by reacting Compound (r-1) readilyavailable with diethyl acetylaminomalonate in the presence of a base,which is conventional in preparing amino acid derivatives. Next,protective benzyl is removed in a conventional manner to convertCompound (r-2) into Compound (r-3). Compound (r-3) is heated todecarboxylate under acidic conditions to prepare Compound (r-4). Afterthe carboxy is protected in the form of the methyl ester, the hydroxy isconverted into acetylthio under mild conditions in a conventionalmanner, using as reactants 2-fluoro-1-methylpyridiniump-toluenesulfonate, thioacetic acid and triethylamine. Thus, Compound(r-5) is prepared. By removing methoxy and S-acetyl protective groupsunder mild basic conditions, Compound (r) is obtained from Compound(r-5).

Compound (s) can be easily prepared by the procedures which comprisesconverting COOH of thiol-protected L-cysteine to cyano, reacting withsodium azide to convert into 5-tetrazolyl and removing the protectivegroup to liberate thiol.

Compound (t) may be readily prepared by the process described inChemistry Letters, 133-136 (1977), using 3-pyridinepropanol as astarting compound.

Compound (u) may be readily prepared by reacting thiol-protectedCompound (t) with methyl iodide and then liberating thiol by removingthe protective group from the resulting pyridinium iodide.

[C] Processes for preparing the compounds of formula [1C]

The compounds of general formula [1C] wherein X_(c) is S, C or NH areprepared by reacting cyclopentenone derivatives (the carbonyl at the1-position may be adequately protected; hereinafter simply referred toas reactive derivatives) represented by general formula [2C]:

(wherein U is a leaving group and, Z1′_(c), Z2′_(c) and Z3′_(c) have thesame significance as defined in Z1_(c), Z2_(c) and Z3_(c) but when thegroup contains a functional group, the functional group may be suitablyprotected), with compounds of general formula [3C]:

HX_(c)2−Y′_(c)  [3C]

(wherein X_(c)2 is S, O or NH and Y′_(c) has the same significance asdefined for Y_(c) but where it contains a functional group, thefunctional group may be properly protected), and when required, removingthe protective group. Preferred examples of the reactive derivativesdescribed above are compounds of general formulas [4C], [5C], [6C], [7C]and [8C].

In the formulas above, R16 is an aliphatic hydrocarbon group having 1 to10 carbon atoms, such as an alkyl, an alkenyl or an aryl. These groupsmay be substituted or unsubstituted. Where a substituent(s) are afunctional group(s), the functional groups may be protected withprotective groups, if necessary and desired. R17 and R18 each representshydrogen or an aliphatic hydrocarbon group having 1 to 10 carbon atoms,for example, an alkyl, an alkenyl or an aryl. These groups may besubstituted or unsubstituted. Where a substituent(s) are a functionalgroup(s), the functional groups may be protected with protective groups,if necessary and desired. Z1′_(c), Z2′_(c) and Z2′_(c) have the samesignificance as defined above.

Examples of the compounds of general formulas [4C], [5C], [6C], [7C] and[8C] are illustrated below.

(a)2-[(2R)-(2-acetylamino-2-methoxycarbonyl)ethylsulfonyl]methyl-4-tert-butyldimethylsiloxy-2-cyclopentan-1-one

(b) 2-methylidene-4-tert-butyldimethylsiloxy-2-cyclopentan-1-one

(c) 2-diethylaminomethyl-4-tert-butyldimethylsiloxy-2-cyclopenten-1-one

(d) 3-acetoxy-2-benzenesulfonylmethyl-2-cyclopenten-1-one

In the general formula [3C] wherein X_(c) is S, the compounds of formula[3C] include the following:

(e) (2R)-2-acetylamino-2-carboxyethanethiol

(f) (2R)-2-acetylamino-2-methoxycarbonylethanethiol

For conducting the above reaction, any condensation process may be usedso long as the compounds of formula [2C] can be condensed with thecompounds of formula [3C]. The reaction is carried out generally in anorganic solvent, water or a mixture thereof. As the organic solventthere may be employed an aromatic hydrocarbon such as benzene, toluene,etc.; an alcohol such as methanol, ethanol, etc.; an ether such astetrahydrofuran, diethyl ether, etc.; a halogenated hydrocarbon such asmethylene chloride, chloroform, etc.; a ketone such as acetone, methylethyl ketone, etc.; an aprotic polar solvent such as dimethyl sulfoxide,dimethylformamide, etc. Preferred examples of the solvent are an ethersuch as tetrahydrofuran or diethyl ether, a halogenated hydrocarbon suchas methylene chloride or chloroform, a ketone such as acetone or methylethyl ketone, an aprotic polar solvent such as dimethyl sulfoxide ordimethylformamide, or a mixture of such solvent and water. The reactionproceeds generally in the presence of an acid or a base or in theabsence or any catalyst, preferably under basic conditions usinginorganic bases, e.g., potassium hydroxide, sodium hydroxide, potassiumcarbonate, sodium carbonate, sodium hydride, etc., or organic bases suchas triethylamine, 1,8-diazabicyclo[5.4.0]-undeca-7-ene, etc. Thesereactants are employed in an amount of approximately 0.1 to 20-foldmols, preferably approximately 0.5 to 5-fold mols. The reactiontemperature is not particularly limited so that the reaction may becarried out under cooling, at ambient temperature or with heating.Preferably, the reaction is performed at a temperature between 0° C. and100° C. The compounds of formula [2C] may be reacted with the compoundsof formula [3C] in an equimolar amount. Practically, the compounds offormula [3C] may be used in an excess amount, e.g., 1 to 2-fold mols.The reaction is performed in 0.1 to 200 hours, preferably 0.1 to 72hours.

Where Compound (a) or Compound (b) is selected as the compounds offormula [2C], the resulting condensation product is further dehydratedafter removal of the protective group for the hydroxy to give thedesired cyclopentenone derivative. As reactants for the removal of theprotective group and the dehydration, an acid, an acidic resin, a Lewisacid or a fluorine reagent may be employed. The acid that can be usedincludes an inorganic acid such as hydrochloric acid or sulfuric acidand an organic acid such as p-toluenesulfonic acid and acetic acid. Asthe acidic resin, preferred is Dowex 50. Boron fluoride etherate or thelike is advantageously used as the Lewis acid. The fluorine reagentincludes tetrabutylammonium fluoride and hydrogen fluoride.

In the compounds of general formula [2C] wherein X_(c) is N, that is,where the compounds of formula [7C] are condensed with the compounds offormula [3C], the objective condensation product can be prepared bymethylating or oxidizing the nitrogen of the compounds shown by formula[7C] and then reacting the methylated or oxidized product with thecompounds of formula [3C]. Examples of the methylating agent are amethyl halide and dimethyl sulfate, preferably methyl iodide. Theoxidizing agent includes an organic peracid such as m-chloroperbenzoicacid, hydrogen peroxide, an organic peroxide, etc., preferably anorganic peracid such as m-chloroperbenzoic acid, or hydrogen peroxide.

The compounds of formula [1C] wherein X_(c) is SO₂ may be prepared byoxidizing the compounds of formula [1C] wherein X_(c) is S. Theoxidizing agent suitable for use includes an organic peracid such asm-chloroperbenzoic acid, etc., an inorganic oxidizing agent such asmanganese dioxide, chromic acid, ruthenium tetroxide, etc., hydrogenperoxide, an organic peroxide, preferably an organic peracid such asm-chloroperbenzoic acid.

The compounds of formula [1C] wherein X_(c) is SO may be prepared byoxidizing the compounds of formula [1C] wherein X_(c) is S. Theoxidizing agent suitable for use includes an organic peracid such asm-chloroperbenzoic acid, etc., an inorganic oxidizing agent such asmanganese dioxide, chromic acid, ruthenium tetroxide, etc., hydrogenperoxide, an organic peroxide, a halogen type oxidizing agent such asperiodic acid, etc.

For example, Compound (a) and Compound (b) described above may beprepared as follows.

Starting Compound (c) is known and commercially available from, e.g.,Nissan Chemical Co., Ltd. Compound (c) may be converted into Compound(a-1) under reaction conditions similar to those used for thecondensation of the compounds of formula [2C], wherein Xc is N. NextCompound (a-2) may be produced under reaction conditions similar tothose for the oxidation to SO₂ described above. The carbon-carbon doublebond of Compound (a-2) may be reduced in a conventional manner to giveCompound (a). As the reducing agent there may be employed an alkalinemetal reducing agent, an organic tin reducing agent, an organic siliconreducing agent, a catalytic hydrogenation reducing agent, etc.,preferably a catalytic hydrogenation reducing agent such aspalladium-carbon, etc. Compound (b) may be prepared by maintainingCompound (a) under basic conditions. Reactants that may be used for thebasic conditions are an inorganic base such as potassium hydroxide,sodium hydroxide, potassium carbonate, sodium carbonate, sodium hydride,etc., and an organic base such as triethylamine,1,8-diazabicyclo[5.4.0]-undeca-7-ene, etc., preferably an organic basesuch as triethylamine or 1,8-diazabicyclo[5.4.0]-undeca-7-ene.

Compound (d-1) is known by literature and may be prepared, e.g., by themethod described J. Org. Chem., 58, 3953-3959 (1993). By acetylation ofCompound (d-1) in a conventional manner, Compound (d) may be prepared.

The compounds of formula [4C] through [8C] other than Compounds (a) to(d) may be prepared by appropriately modifying the above procedures forpreparing Compounds (a) to (d).

Compound (e) is commercially available from, e.g., Tokyo Kasei K.K.Compound (f) is readily prepared by heating Compound (e) in methanol inthe presence of an acidic catalyst. As the acidic catalyst, there are anorganic acid such as hydrochloric acid, sulfuric acid, etc., an organicacid such as p-toluenesulfonic acid, or a Lewis acid such as boronfluoride etherate, etc., preferably an organic acid such asp-toluenesulfonic acid.

[D] Processes for preparing the compounds of formula [1D]

The compounds of general formula [1D] wherein X_(D) is S, O or NH areprepared by reacting ketone derivatives (the carbonyl at the 1-positionmay be protected appropriately; hereinafter simply referred to asreactive derivatives) represented by general formula [2D]:

(wherein U is a splitting-off group and, A′_(D), B′_(D) and Z′_(D) havethe same significance as defined in A_(D), B_(D) and Z_(D) but where thegroup contains a functional group, the functional group may be protectedsuitably), with compounds of general formula [3D]:

HX_(D)2−Y″_(D)  [3D]

(wherein X_(D)2 is S, O or NH and Y′_(D) has the same significance asdefined for Y_(D) but where it contains a functional group, thefunctional group may be properly protected), and when required, removingthe protective group. Preferred examples of the reactive derivativesdescribed above are compounds of general formulas [4D], [5D], [6D], [7D]and [8D].

In the formulas above, R16 is an aliphatic group having 1 to 10 carbonatoms, such as an alkyl, an alkenyl or an aryl. These groups may besubstituted or unsubstituted. Where a substituent(s) are a functionalgroup(s), the functional groups may be appropriately protected withprotective groups. Each of R17 and R18, which may be the same ordifferent, independently represents an alkyl having 1 to 4 carbon atomsor R17 and R18 are combined together to form a piperazine ring or apyrrolidine ring. A′_(D), B′_(D) and Z′_(D) have the same significanceas defined above. R16 and Z′_(D) may also be combined together to form aγ-butyrolactone ring.

Examples of the compounds of general formulas [4D], [5D], [6D], [7D] and[8D] are shown below.

(a) 4-acetyl-γ-butyrolactone

(b) 3-methylidene-4-oxo-1-n-pentanoic acid

(c) trans-2,3-bis(acetoxymethyl)-1-cyclobutanone

(d) 3-acetoxymethyl-2-methylidene-1-cyclobutanone

(e) 3-ethoxycarbonyl-2-methanesulfoxymethyl-1-cyclobutanone

(f) 3-ethoxycarbonyl-2-methylidene-1-cyclobutanone

(g)2-[(2,3-O-isopropylidene)propylsulfonyl]-methyl-3-oxo-1-cyclohexanecarboxylicacid

(h) 2-methylidene-3-oxo-1-cyclohexanecarboxylic acid

(i) 4-oxo-4-phenyl-3-(1-piperidyl)methylbutyric acid

(j) 4-oxo-4-(3-pyridyl)-3-(1-piperidyl)methylbutyric acid

(p) 4-(1-piperidyl)methyl-5-oxo-5-phenylpentanoic acid

In the compounds of formula [3D] wherein X_(D) is S, the compounds offormula [3D] include the following:

(q) (2R)-2-acetylamino-2-carboxyethanethiol

(r) (2R)-2-acetylamino-2-methoxycarbonylethanethiol

(s) 2,3-dihydroxypropane-1-thiol (alphathioglycerine)

For conducting the above reaction, any condensation process may be usedso long as the compounds of formula [2D] can be condensed with thecompounds of formula [3D]. The reaction is carried out generally in anorganic solvent, water or a mixture thereof. As the organic solventthere may be employed an aromatic hydrocarbon such as benzene, toluene,etc.; an alcohol such as methanol, ethanol, etc.; an ether such astetrahydrofuran, diethyl ether, etc.; a halogenated hydrocarbon such asmethylene chloride, chloroform, etc.; a ketone such as acetone, methylethyl ketone, etc.; an aprotic polar solvent such as dimethyl sulfoxide,dimethylformamide, etc. Preferred examples of the solvent to be used arean ether such as tetrahydrofuran or diethyl ether, a halogenatedhydrocarbon such as methylene chloride or chloroform, a ketone such asacetone or methyl ethyl ketone, an aprotic polar solvent such asdimethyl sulfoxide or dimethylformamide an alcohol such as methanol orethanol, or a mixture of such solvent and water. The reaction proceedsgenerally in the presence of an acid or a base or in the absence or anycatalyst, preferably under basic conditions. Where no catalyst is used,the reaction may sometimes proceed with heating. Reactants used to makethe reaction system are an inorganic base such as potassium hydroxide,sodium hydroxide, potassium carbonate, sodium carbonate, sodium hydride,etc., or an organic base such as triethylamine,1,8-diazabicyclo[5.4.0]-undeca-7-ene, etc. These reactants are employedin an amount of approximately 0.1 to 20-fold mols, preferablyapproximately 0.5 to 5-fold mols. The reaction temperature is notparticularly limited so that the reaction may be carried out undercooling, at ambient temperature or with heating. Preferably, thereaction is performed at a temperature between −20° C. and 130° C. Wherethe condensation is performed in the absence of a catalyst, thetemperature is preferably between 30° C. and 200° C. The compounds offormula [2D] may be reacted with the compounds of formula [3D] in anequimolar amount. Practically, the compounds of formula [3D] may be usedin an excess amount, e.g., 1 to 2-fold mols. The reaction is performedin 0.1 to 200 hours, preferably 0.1 to 72 hours.

The compounds of formula [1D] wherein X_(D) is SO₂ may be prepared byoxidizing the compounds of formula [1D] wherein X_(D) is S. Theoxidizing agent suitable for use in the oxidation includes an organicperacid such as m-chloroperbenzoic acid, etc., an inorganic oxidizingagent such as permanganate, chromic acid, ruthenium tetroxide, etc.,hydrogen peroxide, an organic peroxide, etc., preferably an organicperacid such as m-chloroperbenzoic acid.

The compounds of formula [1D] wherein X_(D) is SO may be prepared byoxidizing the compounds of formula [1D] wherein X_(D) is S. Theoxidizing agent suitable for use in the oxidation includes an organicperacid such as m-chloroperbenzoic acid, etc., an inorganic oxidizingagent such as manganese dioxide, chromic acid, ruthenium tetroxide,etc., hydrogen peroxide, an organic peroxide, a halogen type oxidizingagent such as periodic acid, etc.

For example, Compound (a) and Compound (b) described above may beprepared as follows.

Compound (a) is known and may be prepared, e.g., by the method describedin Bull. Chem. Soc. Jpn., 32, 1282 (1959). Compound (b) is also knownand may be prepared, e.g., by the process disclosed in Japanese PatentKOKOKU Showa 37-5911. Compound (b) may be prepared by maintainingCompound (a) under acidic or basic conditions. Reactants used for theabove reaction are an inorganic base such as potassium hydroxide, sodiumhydroxide, potassium carbonate, sodium carbonate, sodium hydride, etc.,an organic base such as triethylamine,1,8-diazabicyclo[5.4.0]-undeca-7-ene, etc., an in-organic acid such ashydrochloric acid, sulfuric acid, etc., and an organic acid such asp-toluenesulfonic acid, preferably an organic base such astriethylamine, 1,8-diazabicyclo[5.4.0]-undeca-7-ene or an inorganic acidsuch as sulfuric acid.

Compounds (c) and (d) can be prepared as follows.

Compound (c) analogues are known and described in, e.g., TetrahedronLett., 6453 (1989) and Compound (c) itself can be readily prepared bythe process described therein. Compound (d) can be prepared bymaintaining Compound (c) under basic conditions. Reactants that may beadvantageously used for the reaction are an inorganic base such aspotassium hydroxide, sodium hydroxide, potassium carbonate, sodiumcarbonate, sodium hydride, etc., and an organic base such astriethylamine, 1,8-diazabicyclo[5.4.0)-undeca-7-ene, etc., preferably anorganic base such as triethylamine or1,8-diazabicyclo(5.4.0]-undeca-7-ene.

Compounds (e) and (f) may be prepared as follows.

Compound (e-1) is known and may be prepared, e.g., by the processdescribed J. Org. Chem., 53, 3841 (1988). To convert Compound (e-1) toCompound (e) and then Compound (f), the process described in J. Org.Chem., 53, 611 (1988) is applied by appropriate modification. That is,Compound (e-2) can be prepared by treating Compound (e-1) with a baseand treating the anions generated with formaldehyde. As the base, theremay be used LDA, n-butyl lithium, KHMDS, sodium hydride, etc.,preferably LDA. Formaldehyde is preferably reacted as a monomer aftercracking of its polymer. Compound (e) can be prepared by mesylation ofCompound (e-2) in a conventional manner. More specifically, Compound(e-2) is reacted with mesyl chloride as a reactant in methylenechloride, while ice-cooling, in the presence of triethylamine as a base.Then Compound (f) can be produced via Compound (e) spontaneously underthe same system at a time.

Compounds (g) and (h) may be prepared as follows.

Compound (g-1) and Compound (g-2), which are known by literature andcommercially available, are subjected to Diels-Alder reaction in aconventional manner to give Compound (g-3). Compound (g-3) is convertedinto Compound (g-4) through the reduction with lithium aluminum hydrideand the removal of silyl protective group. The allyl alcohol moiety inCompound (g-4) is oxidized with manganese dioxide in a conventionalmanner. The hydroxy groups of resulting Compound (g-5) is acetylated inacetic anhydridepyridine as a reactant followed by the reduction of thedouble bond in the ring with palladium-carbon. Compound (g-6) can thusbe readily prepared.

The reaction of Compound (g-6) to give Compound (g-7) can be performedunder conditions similar to those used to condense the compounds offormula [2D] and the compounds of formula [3D]. In this reaction,alpha-thioglycerine is employed as the compound of formula [3D]. Next,the 1,2-diol group of Compound (g-7) is protected with a protectivegroup such as an acetal, a ketal or an ortho-ester. Preferably, Compound(g-7) is reacted with acetone or its activated derivative in thepresence of an acid catalyst to give Compound (g-8), where the 1,2-diolis protected with the isopropylidene. Subsequently, the acetyl isremoved by alkaline hydrolysis in a conventional manner to give Compound(g-9). The sulfide of Compound (g-9) is oxidized to the sulfone. Thus,Compound (g-10) is prepared. The reaction is carried out under suchconditions that are similar to those used for the oxidation but thehydroxy is not oxidized. Where the hydroxy is oxidized to COOH, Compound(g) can be prepared in one step. Compound (g) can be prepared byoxidizing the hydroxy with an oxidizing agent. The oxidizing agent thatcan be used includes an inorganic acid such as a permanganate, chromicacid, etc., preferably chromic acid. Compound (h) can be prepared bymaintaining Compound (g) under basic conditions similar to those used tocondense the compounds of formula [2D] and the compounds of formula[3D], without adding the compounds of formula [3D] to the reactionsystem. Reactants that may be advantageously used for the reaction arean inorganic base such as potassium hydroxide, sodium hydroxide,potassium carbonate, sodium carbonate, etc., and an organic base such astriethylamine, 1,8-diazabicyclo[5.4.0]-undeca-7-ene, etc., preferably anorganic base such as triethylamine.

Compound (i) is known and may be prepared, e.g., by the processdescribed in J. Chem. Soc. (C), 2308 (1967). Compound (j) may beprepared by reacting the corresponding aldehyde with an acrylic acidderivative in the presence of a catalyst such as sodium cyanide or3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride, etc. (Chem.Ber., 109, 289, 541 (1976)) and then subjecting the reaction product toMannich reaction. Compound (p) can be prepared by subjecting known5-oxo-5-phenylpentanoic acid to Mannich reaction.

Compounds (q) and (s) are commercially available from, e.g., Tokyo KaseiK.K. Compound (r) can be readily prepared by heating Compound (q) inmethanol in the presence of an acid catalyst. As the acidic catalyst,there are an in-organic acid such as hydrochloric acid, sulfuric acid,etc., an organic acid such as p-toluenesulfonic acid, or a Lewis acidsuch as boron fluoride etherate, etc., preferably an organic acid suchas p-toluenesulfonic acid.

[E] Process for preparing the compound of formula [1E]

The compound of formula [1E] (hereinafter sometimes referred to asphysiologically active substance NA) may be prepared by culturing NA32176-producing strain belonging to the genus Streptomyces to produceand accumulate the physiologically active substance NA32176A andcollecting the physiologically active substance NA32176A from theculture solution. A representative examples of bacteria capable ofproducing the physiologically active substance NA32176A has thefollowing microbiological and physiological properties.

1. Morphological properties

When observed after incubation at 27° C. for 2 weeks, aerial mycelia aresimply branched and spiral or hook-like at the top. Neither sporangianor verticillate branch are noted. No zoospore is noted, either. Thesurface of spores is flat or rough. The spores are cylindrical and havea size of 0.7 to 0.9×1.3 μm. The spores are formed in more than 20chains.

2. Growth in various media

Growth conditions at 27° C. for 2 weeks in various media are shown inTable 1 below.

TABLE 1 Aerial Substrate Soluble Medium Growth Mycelium Mycelium PigmentSucrose- moderate moderate, colorless none nitrate brownish ˜light agarmedium white yellow ˜light brownish grey ˜black (hygroscopic) Glucose-moderate abundant, light yellow slightly asparagine- brownish ˜brownbrownish agar medium white˜light brownish grey ˜black (hygroscopic)Glycerine- moderate abundant, colorless˜ brownish asparagine- brownishlight yellow agar medium white˜ (ISP 5 med.) light brownish gray˜black(hygroscopic) Starch- good moderate, light yellow slightly inorganicbrownish ˜brownish salt-agar white˜light medium brownish gray (ISP 4med.) ˜black (hygroscopic) Tyrosine- good moderate, light yellowbrownish agar brownish medium white˜light (ISP 7 med) brownish gray˜black (hygroscopic) Nutrient- moderate moderate, light yellow slightlyagar white brownish medium Yeast- good abundant, colorless slightlymaltose- brownish brownish agar medium white˜light (ISP 2 med.) brownishgray ˜black (hygroscopic) Oatmeal- moderate moderate, colorless noneagar brownish medium white˜light (ISP 3 med.) brownish gray ˜black(hygroscopic)

3. Physiological properties

1) Optimum growth temperature range: 24˜37° C.

2) Reduction of nitrate: negative

3) Liquefaction of gelatin (glucose-peptone-gelatin medium, 20° C.) :pseudo-positive

4) Hydrolysis of starch (starch-inorganic salt-agar

medium): positive

5) Solidification of skimmed milk: negative

6) Peptonization of skimmed milk: positive

7) Formation of melanoid pigment: negative

4. Assimilation of carbon sources (Pridham-Gottlieb agar medium)

L-Arabinose + D-Xylose + D-Glucose + D-Fructose + Sucrose + Inositol −L-Rhamnose − Raffinose + D-Mannitol +

5. Diaminopimelic acid in cell wall

LL-diaminopimelic acid

From the foregoing results, the cell wall of this strain isLL-diaminopimelic acid; according to International Streptomyces Project(abbreviated as ISP), the morphology of spore-forming mycelium belongsto section spirales. The surface of spores is flat or rough; the myceliaare of gray color-series and hygroscopic. Melanin-like pigment is notproduced. The substrate mycelium shows light yellow or light brown. Thestrain assimilates as carbon sources L-arabinose, D-glucose, D-fructose,sucrose, raffinose, D-mannose, D-mannitol and D-xylose.

Based on the foregoing properties, survey was made according to R. E.Buchanan & N. E. Gibbons, Bergey's Manual of Determinative Bacteriology,8th edition, 1974; the strain NA32176 was found to belong to the genusStreptomyces. Therefore, the strain was named Streptomyces sp. NA32176.

The strain was deposited in the National Institute Bioscience andHuman-Technology Agency of Industrial Science and Technology (No. 1-3,Higashi 1-chome, Tsukubashi, Ibaraki, Japan) on Aug. 8, 1997 andreceived FERM P-16372 as an accession number. Then the deposition wastransferred into an international deposition under the Budapest Treatyon Jul. 7, 1998 and received FERM BP-6411 as an accession number.

The strain capable of producing the physiologically active substanceNA32176A of the present invention having the aforesaid neurondifferentiation promoting activity belongs to the genus Streptomyces.Streptomyces sp. NA32176 (Accession No. FERM P-16372 in the NationalInstitute Bioscience and Human-Technology Agency of Industrial Scienceand Technology; International Accession No. FERM BP-6411), which wasisolated by the present inventors, is one example of the strains usedmost effectively in this invention.

The strain belonging to the genus Streptomyces employed in the presentinvention are susceptible to change in their properties, like otherstrains belonging to the genus Streptomyces, and thus readily mutated byartificial mutation using, e.g., UV rays, X rays or chemicals. Anymutant can be used for the present invention so long as it is capable ofproducing the physiologically active substance NA32176A of the presentinvention.

For producing the physiologically active substance NA32176A according tothe present invention, the strain described above is aerobicallyincubated in a medium containing nutrients Streptomyces can assimilate.As nutrient sources, known nutrients heretofore used for the incubationof Streptomyces may be employed. As carbon sources, there are glucose,fructose, glycerine, sucrose, dextrin, galactose, organic acids, etc.,that may be used, alone or in combination thereof.

As inorganic and organic nitrogen sources, there are ammonium chloride,ammonium sulfate, urea, ammonium nitrate, sodium nitrate, peptone, meatextract, yeast extract, dry yeast, corn steep liquor, soybean powder,cotton seed lees, Casamino acid, bacto-soyton, soluble vegetableprotein, oatmeal, etc., which may be employed, alone or in combination.

If necessary and desired, inorganic salts such as sodium chloride,calcium carbonate, magnesium sulfate, copper sulfate, iron sulfate, zincsulfate, manganese chloride, phosphoric acid salts, etc. may also besupplemented to the system. Furthermore, organic materials such as aminoacids, vitamins, nucleic acids and inorganic substances may also besupplemented appropriately in the culture system.

For incubation, liquid culture, especially deep spinner culture is mostsuitable. It is desired to perform incubation at a temperature of 20° C.to 40° C. at a pH range of slightly acidic to slightly alkaline nature.

In liquid culture, the incubation generally for 3 to 5 days results inthe production and accumulation of the substance NA32176A in the culturebroth. The incubation is terminated when the amount of the substanceproduced reached the maximum. The cells are then separated from themedium by filtration and the product is purified and isolated.

The purification and isolation of the product from the filtrate may beeffected by methods conventionally applied to the separation andpurification of a metabolite from a microorganism from the culturedcells.

That is, the culture broth is separated into the filtrate and the cellsby conventional filtration. The filtrate is passed through a DIAIONHP-20 (trademark, Mitsubishi Chemical Industries, Ltd.) column underalkaline conditions to adsorb the objective substance. After washingwith water, the column was eluted in a linear gradient from water to 80%hydrated methanol. The eluted active fraction is concentrated andmethanol is distilled off. The resulting concentrate is extracted withn-butanol under acidic conditions of hydrochloric acid.

The n-butanol phase is concentrated in vacuum. The concentrate is thensubjected to Sephadex LH-20 (trademark, Pharmacia Biotech) columnchromatography (moving phase: methanol). The collected active fractionsare concentrated and dissolved in a mixture of ethyl acetate-water(1:1). The solution is subjected to centrifugal liquid-liquid partitionchromatography (manufactured by Sanki Engineering K.K., CPC-LLB-M) usingas a fixing phase the lower layer of the ethyl acetate-water mixtureabove. After washing with the upper layer of the mixture, the activefraction is reversely eluted with the lower layer. Further SephadexLH-20 column chromatography (moving phase: methanol) gives NA32176A.

Physicochemical properties of the thus obtained physiologically activesubstance NA32176A are shown below.

1) Appearance: white powder

2) Molecular weight: 418

3) Molecular formula: C18H₃₀N₂O₇S

(determined by high resolution mass spectrum)

4) Solubility:

soluble in a lower alcohol, water or dimethylsulfoxide;

insoluble in hexane or petroleum ether

5) Rf value by ODS thin layer chromatography:

0.7 with a developing solvent of n-butanol:acetic acid:water (4:1:2)

6) UV absorption spectrum:

showing terminal absorption in water

7) IR absorption spectrum:

The spectrum measured with potassium tablet is shown in FIG. 1.

8) Hydrogen nuclear magnetic resonance spectrum:

The spectrum measured in heavy water is shown in FIG. 2.

9) Carbon nuclear magnetic resonance spectrum:

The spectrum measured in heavy water is shown in FIG. 3. Chemical shiftdata is shown below.

δ (ppm) 223.5 (s), 180.1 (s), 176.4 (s), 175.1 (s), 77.0 (d), 69.6 (t),53.4 (d), 47.7 (d), 39.8 (s), 39.7 (t), 38.9 (t), 36.7 (t), 36.5 (t),32.5 (t), 31.0 (t), 25.7 (t), 21.8 (q), 20.3 (q)

10) Color-forming reaction:

positive with phosphorus molybdate and palladium chloride

The physiologically active substance NA32176A represented by formula[1E] may also be prepared in a manner similar to the processes forproducing the compounds of formula [1B] described above.

In more detail, the physiologically active substance NA32176A may bereadily produced by using pantetheine (a product of cysteamine andpantothenic acid bound to each other) as the compound of formula [3B]and condensing pantetheine under conditions similar to those used withCompounds (a) through (f).

Pantetheine is known by Helv. Chim. Acta, 35, 1903 (1952) and may bereadily prepared by hydrolysis of pantetheine S-benzoyl ester underalkaline conditions in a conventional manner.

[F] Processes for preparing the compounds of formula [1F]

The compounds of general formula [1F] may be prepared by reactingcompounds of general formula [2F]:

(wherein A′_(F), B′_(F) and Z′_(F) have the same significance as definedin A_(F), B_(F) and Z_(F) but where the group contains a functionalgroup, the functional group may be protected suitably), with compoundsof general formula [3F]:

HNX′_(F)Y′_(F)  [3F]

(wherein X′_(F) and Y′_(F) have the same significance as defined forX_(F) and Y_(F) but where it contains a functional group, the functionalgroup may be properly protected), and when required, removing theprotective group. Most of the compounds of formula [3F] are commerciallyavailable. Specific examples of the compounds [3F] are piperidine,pyrrolidine, morpholine, N-methylpiperazine, N-phenylpiperazine,diethylamine, di-n-propylamine, diisopropylamine, etc.

For conducting the above reaction, any condensation process may be usedso long as the compounds of formula [2F] can be condensed with thecompounds of formula [3F]. The reaction is carried out generally in anorganic solvent, water or a mixture thereof. As the organic solventthere may be employed an aromatic hydrocarbon such as benzene, toluene,etc.; an alcohol such as methanol, ethanol, etc.; an ether such astetrahydrofuran, diethyl ether, etc.; a halogenated hydrocarbon such asmethylene chloride, chloroform, etc.; a ketone such as acetone, methylethyl ketone, etc.; an aprotic polar solvent such as dimethyl sulfoxide,dimethylformamide, etc. Preferred examples of the solvent to be used arean ether such as tetrahydrofuran or diethyl ether, a halogenatedhydrocarbon such as methylene chloride or chloroform, a ketone such asacetone or methyl ethyl ketone, an aprotic polar solvent such asdimethyl sulfoxide or dimethylformamide, an alcohol such as methanol orethanol, or a mixture of such solvent and water. The reaction proceedsgenerally in the presence of a base or in the absence or any catalyst.Reactants used to keep the basic conditions are an inorganic base suchas potassium hydroxide, sodium hydroxide, potassium carbonate, sodiumcarbonate, sodium hydride, etc., or an organic base such astriethylamine, 1,8-diazabicyclo[5.4.0]-undeca-7-ene, etc. Thesereactants are employed in an amount of approximately 0.1 to 20-foldmols, preferably approximately 0.5 to 5-fold mols. The reactiontemperature is not particularly limited so that the reaction may becarried out under cooling, at ambient temperature or with heating.Preferably, the reaction is performed at a temperature between −50° C.and 150° C. The compounds of formula [2F] may be reacted with thecompounds of formula [3F] in an equimolar amount. Practically, thecompounds of formula [3F] may be used in an excess amount, e.g., 1 to2-fold mols. The reaction is performed in 0.1 to 240 hours, preferably0.1 to 96 hours.

The compounds of general formula [1F] may be readily prepared byreacting compounds of general formula [4F]:

(wherein A′_(F), B′_(F) and Z′_(F) have the same significance as definedin A_(F), B_(F) and Z_(F) but where the group contains a functionalgroup, the functional group may be protected suitably), with compoundsof general formula [3F]:

HNX′_(F)Y′_(F)  [3F]

(wherein X′_(F) and Y′_(F) have the same significance as defined forX_(F) and Y_(F) but where it contains a functional group, the functionalgroup may be properly protected) in the presence of formaldehyde or anequivalent thereto, and when required, removing the protective group.With respect to the details of the compounds of formula [3F], theforegoing description applies thereto.

The condensation process of the compounds of formula [4F] and thecompounds of formula [3F] in the presence of formaldehyde or anequivalent thereto is called Mannich reaction, which details are alreadydescribed in various reviews (e.g., Tetrahedron, 46, 1791 (1990),Synthesis, 1973, 703). The reaction is carried out generally in anorganic solvent, water or a mixture thereof. As the organic solventthere may be employed an aromatic hydrocarbon such as benzene, toluene,etc.; an alcohol such as methanol, ethanol, etc.; an ether such astetrahydrofuran, diethyl ether, etc.; a halogenated hydrocarbon such asmethylene chloride, chloroform, etc.; a ketone such as acetone, methylethyl ketone, etc.; an aprotic polar solvent such as dimethyl sulfoxide,dimethylformamide, etc. Preferred examples of the solvent are an ethersuch as tetrahydrofuran or diethyl ether, a halogenated hydrocarbon suchas methylene chloride or chloroform, a ketone such as acetone or methylethyl ketone, an aprotic polar solvent such as dimethyl sulfoxide ordimethylformamide, an alcohol such as methanol or ethanol, or a mixtureof such solvent and water. The reaction proceeds generally in thepresence of any catalyst. If necessary and desired, an acid may be usedas a catalyst. Example of the formaldehyde equivalent are 1,3,5-trioxaneand bis(dimethylamino)methane. Formaldehyde and its equivalents may beused in an amount of approximately 0.9 to 100-fold mols, preferably 1 to20-fold mols. The reaction temperature is not particularly limited sothat the reaction may be carried out under cooling, at ambienttemperature or with heating. Preferably, the reaction is performed at atemperature between 0° C. and 200° C. The compounds of formula [4F] maybe reacted with the compounds of formula [3F] in an equimolar amount.Practically, the compounds of formula [3F] may be used in an excessamount, e.g., 1 to 2-fold mols. The reaction is performed in 0.1 to 360hours, preferably 0.1 to 120 hours.

The compounds of general formula [1F] may be readily prepared byreacting compounds of formula [5F]:

(wherein A′_(F), B′_(F) and Z′_(F) have the same significance as definedin A_(F), B_(F) and Z_(F) but where the group contains a functionalgroup, the functional group may be protected suitably, and U is aleaving group and the carbonyl at the 1-position may be suitablyprotected), with compounds of general formula [3F]:

HNX′_(F)Y′_(F)  [3F]

(wherein X′_(F) and Y′_(F) have the same significance as defined forX_(F) and Y_(F), and where it contains a functional group, thefunctional group may be properly protected), and when required, removingthe protective group. The compounds of formula [3F] are detained hereinabove. The reaction conditions used for the reaction are similar tothose for the reaction of the compounds of formula [2F] and [3F].

Preferred examples of the leaving group are chloride, bromine, iodine,methanesulfonyloxy, chloromethanesulfonyloxy,trifluoromethanesulfonyloxy, chloromethanesulfonyloxy and(2,3-O-isopropylidene)propylsulfonyl.

Specific examples of the compounds of formula [5F] are listed below.

(a)2-[(2,3-O-isopropylidene)propylsulfonyl]methyl-3-oxo-1-cyclopentanecarboxylicacid

(b)2-[(2,3-O-isopropylidene)propylsulfonyl]methyl-3-methoxycarbonylcyclopentanone

As a representative process for preparing the compounds of formula [2F]is described below. That is, the compounds of formula [2F] may bereadily prepared by reacting the compounds of formula [4F]:

(wherein A′_(F), B′_(F) and Z′_(F) have the same significance as definedin A_(F), B_(F) and Z_(F) but where the group contains a functionalgroup, the functional group may be protected suitably) with formaldehydeor an equivalent thereto in the presence of a secondary amine, ifnecessary, while heating. The reaction conditions are similar to thoseused to react the compounds of formula [4F] with the compounds offormula [3F] described above. Where heating is further required, it ispreferred to heat at 30° C. to 200° C. Alternatively, the compounds offormula [2F] may be readily prepared by producing the compounds offormula [1F] through Mannich reaction, oxidizing the nitrogen of thecompounds [1F] with an oxidizing agent or alkylating the same with analkylating agent to convert into the quaternary salt and then heating,if necessary. The oxidizing agent suitable for use in the oxidationincludes an organic peracid such as m-chloroperbenzoic acid, etc.,hydrogen peroxide, an organic peroxide, etc. The alkylating agentincludes methyl iodide, dimethyl sulfate, ethyl iodide, etc. Heatingconditions optionally performed following the oxidation or alkylationare similar to those described above.

In the compounds of formula [4F] wherein A′_(F) is, for example, analiphatic hydrocarbon group, regioselectivity in the Mannich reactionmight sometimes cause a problem. In that case, the problem may beavoided as follows. For example, known 3-acetylbutyrolactone (Bull.Chem. Soc. Jpn., 32, 1282 (1959)) is kept under acidic or basicconditions to prepare 3-methylidene-4-oxo-1-n-pentaneoic acid. Reactantsused for the reaction are an inorganic base such as sodium hydroxide,etc., an organic base such as triethylamine,1,8-diazabicyclo[5.4.0]-undeca-7-ene, etc., an inorganic acid such ashydrochloric acid, sulfuric acid, etc., and an organic acid such asp-toluenesulfonic acid, preferably an organic base such as triethylamineor 1,8-diazabicyclo[5.4.0]-undeca-7-ene and an inorganic acid such assulfuric acid.

To cope with the regioselectivity problem, other alternatives may beused, such as the process disclosed in J. Chem. Soc. Chem. Commun.,1974, 253 in which highly site-selective reactants for Mannich reactionare used, or the process involving site specific conversion of a ketoneto an enolate followed by introduction of an aminomethylene unit intothe enolate disclosed in Tetrahedron, 46, 987 (1990).

Some of the compounds of formula [4F] are commercially available asreagents. They are, e.g., 4-phenyl-4-oxobutanoic acid,4-(4-methylphenyl)-4-oxobutanoic acid, 4-(4-methoxyphenyl)-4-oxobutanoicacid, 2-methyl-4-oxo-4-phenylbutyric acid, 4-benzoylbutyric acid, etc.The compounds of formula [4F] wherein A_(F) is, e.g., a benzene ring ora benzene ring substituted with an electron donating group may also besynthesized by Friedel-Crafts acylation with maleic anhydride in thepresence of a Lewis acid catalyst such as aluminum chloride (Org.Synthesis, Coll. III, 109 (1955)).

The compounds of formula [4F], wherein A_(F) is other than the groupsdescribed above, or reduction products thereof (alcohol products) may beprepared by a modification of Reformatsky reaction, which involvesreacting the corresponding acid halide of A_(F) or aldehyde with ethylγ-iodopropionate in the presence of zinc (J. Am. Chem. Soc., 109, 8056(1987)). The reduction product may be oxidized to the correspondingketone in a conventional manner to give the compounds of formula [4F].Alternatively, the compounds of formula [4F] may be prepared by reactingthe corresponding aldehyde of A_(F) with acrylic acid derivatives in thepresence of a catalyst such as sodium cyanide or3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride, as described inChem. Ber., 109, Section 289, 541 (1976). Furthermore, the compounds offormula [4F] may be prepared by subjecting the corresponding methylketone of A_(F) to Aldol condensation with glyoxylic acid accompanyingdehydration in vacuo with heating, and reducing the resultingcarbon-carbon double bond in a conventional manner using, e.g., zincpowders-acetic acid, as described in J. Med. Chem., 15, 918 (1972).

The compounds of formula [5F] can be prepared, for example, inaccordance with the following process.

wherein A′_(F), B′_(F) and Z′_(F) have the same significance as definedin A_(F), B_(F) and Z_(F) but where the group contains a functionalgroup, the functional group may be protected suitably, and U is aleaving group and the carbonyl at the 1-position may be suitablyprotected.

The compounds of formula (5F-a) may be prepared from the compounds offormula [4F] by a modification of the known processes for preparing aβhydroxyketone, e.g., by reacting the compounds of formula [4F] withformaldehyde under basic conditions, or by reacting silyl-enolderivatives of the compounds of formula [4F] with formaldehyde underacidic conditions. The compounds of formula [5F] may be readily preparedby reacting the thus obtained compounds of formula (5F-a) with asulfonyl chloride such as p-toluenesulfonyl chloride, if necessary, inthe presence of a base, or by reacting with a halogenating reagent forthe hydroxy, such as thionyl chloride, a triphenylphosphine-halogenatingagent, a triphenylphosphine-diethyl azodicarboxylate-halogenating agent,etc. in a conventional manner. The thus prepared compounds of formula[5F] may be used without isolating the same for the next reaction.

Compounds (a) and (b) described above are the same as Compounds (c) and(d) in the preparation of the compounds of formula [1B] and may beprepared by the processes described for these compounds.

Hereinafter the pharmaceutical properties of the compounds of thepresent invention will be described in more detail.

The compounds of the present invention and pharmacologically acceptablesalts thereof are found to exhibit a potent neuron differentiationpromoting activity. Therefore, the compositions comprising as the activeingredient the compounds of the present invention and pharmacologicallyacceptable salts thereof are effective for promoting or accelerating theneuron differentiation and can thus be used as medicaments for thetreatment of central and peripheral nervous disorders.

Where the compounds of the present invention and pharmacologicallyacceptable salts thereof are used as the neuron differentiationaccelerator, the composition may be used in the form of pharmaceuticalpreparations such as injection, drop, granules, tablets, granulates,fine particles, powders, capsules, liquid, inhalation, suppositories,eye lotion, plaster, ointment, spray, etc., singly or in combinationwith pharmaceutically acceptable additives such as carriers, excipient,diluents, dissolution aids, etc. The route for administration may bechosen from oral and parenteral administration (systemic and localadministration).

The compound of the present invention or a pharmacologically acceptablesalt thereof contained in the pharmaceutical composition variesdepending upon the form of the preparation but preferably in an amountof 0.1 to 100 wt %. A dose is determined depending upon =age, sex, bodyweight, conditions of the patient and purpose of treatment, etc., butgenerally in a range of approximately 0.001 to 5000 mg/kg/day.

Next, the processes for preparing the compounds of the present inventionor pharmacologically acceptable salts thereof and the neurondifferentiation accelerating activity will be described below in moredetail with reference to the following Examples.

EXAMPLE 1 Preparation of4-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-3-oxo-1-cyclopentanecarboxylicAcid (Compound 1A)

(1) Preparation of 1,1-dimethoxy-2,4-bis(methoxycarbonyl)cyclopentane(Compound 1A-B) and 1,1-dimethoxy-2,3-bis(methoxycarbonyl)cyclopentane(Compound 1A-b)

2,4-Bis(methoxycarbonyl)cyclopentanone (Compound 1A-A) is prepared as amixture with 2,3-bis(methoxycarbonyl)cyclopentanone (Compound 1-Aa),e.g., by the process described in J. Org. Chem., 47, 2379 (1982). Byconverting the mixture into 2,4-bis(hydroxymethyl)cyclopentanone and2,3-bis(hydroxymethyl)cyclopentanone, the two compounds can be separatedfrom each other by silica gel column chromatography.

To a mixture (6970 mg, 34.85 mmols) of Compound (1A-A) and Compound(1A-a) were added absolute methanol (35 ml), methyl orthoformate (4.74ml) and p-toluenesulfonic acid monohydrate (165 mg). The mixture wasstirred at room temperature for 18 hours. After toluene (60 ml) wasadded to the reaction mixture, washing was conducted twice withsaturated sodiumhydrogen carbonate (25 ml). The toluene layer was washedwith saturated sodium chloride aqueous solution (50 ml) and concentratedto give a mixture (8334 mg, yield: 97.2%) of1,1-dimethoxy-2,4-bis-(methoxycarbonyl)cyclopentane (Compound 1A-B) and1,1-dimethoxy-2,3-bis(methoxycarbonyl)cyclopentane (Compound 1A-b).

(2) Preparation of 2,4-bis (hydroxymethyl)cyclopentanone (Compound 1A-C)

A solution of a mixture (9676 mg, 39.32 mmols) of Compound (1A-B) andCompound (1A-b) in absolute ether (10 ml) was dropwise added to asuspension of lithium aluminum hydride (3120 mg) in absolute ether (43ml) over an hour under ice cooling. After stirring for 30 minutes, water(3.12 ml), 15% sodium hydroxide (3.12 ml) and water (3.12 ml) werefurther added to the mixture followed by stirring for further 30minutes. Anhydrous sodium sulfate (10 g), ether (55 ml) and HAIFUROSUPER CEL (6 g) were added to the mixture. After stirring for 30minutes, the mixture was filtered. The residue was further extractedtwice with ether (100 ml). All of the ethereal fractions were collectedand concentrated. The resulting residue was dissolved in acetone (37ml). Water (1.85 ml) and 1 N hydrochloric acid (1.85 ml) were added tothe solution. The mixture was stirred for 30 minutes at roomtemperature. After 1 N sodium hydroxide (1.85 ml) was added to thereaction mixture, silica gel (18 g) was added thereto followed byconcentration. The residue was purified by silica gel columnchromatography (550 ml, dichloromethane:methanol=30:1) to give Compound(1A-C, 1310 mg, yield: 23.1%) and Compound (1A-c, 1539 mg, yield:27.0%).

TLC (silica gel:chloroform:methanol=10:1) Compound (1A-C, Rf=0.42),Compound (1A-c, Rf=0.45)

(3) Preparation of 2,4-bis(acetoxymethyl)cyclopentanone (Compound 1A-D)

To Compound (1A-C) (1130 mg, 7.847 mmols) were added anhydrous pyridine(4 ml) and absolute acetic acid (4 ml). The mixture was stirred at roomtemperature for an hour. After the reaction mixture was concentrated,the residue was purified by silica gel column chromatography (150 ml,hexane:ethyl acetate=1:1) to give Compound (1A-D) (1598 mg, yield:89.2%).

1H-NMR (200 MHz, CDCl3) δ: 1.45-1.70 (1H, m), 1.85-2.12 (7H, m),2.15-2.78 (4H, m), 4.00-4.39 (4H, m); MS (FAB, POS) m/z: 229 (M+H)+.

(4) Preparation of4-acetoxymethyl-2-{(2,3-dihydroxy)propylthio}methylcyclopentanone(Compound 1A-E)

Methanol (5 ml), acetone (30 ml) and 1 N sodium hydroxide (6.1 ml) wereadded to Compound (1A-D) (1.4 g, 133 mmols) and alpha-thioglycerine(0.66 g, 133 mmols). The mixture was stirred for 45 minutes. After thepH was adjusted to 7.0 by adding 1 N hydrochloric acid to the reactionsolution, the mixture was concentrated. Saturated sodium chlorideaqueous solution (30 ml) was added to the residue. The mixture wasextracted 5 times with dichloromethane (30 ml). The dichloromethanelayer was dried over anhydrous sodium sulfate followed by concentration.The thus obtained residue was purified by silica gel columnchromatography (300 ml, chloroform:methanol=40:1 to 10:1) to giveCompound (1A-E) (1.5 g, yield: 88.23%).

1H-NMR (200 MHz, CDCl3) δ: 1.50 (1H, m), 1.78 -2.28 (5H, m), 2.35-2.80(8H, m), 2.85-3.08 (1H, m), 3.50-3.63 (1H, m), 3.68-3.90 (2H, m),3.98-4.20 (2H, m); MS (FAB, POS) m/z: 277 (M+H)+.

(5) Preparation of4-acetoxymethyl-2-{(2,3-O-isopropylidene)propylthio}methylcyclopentanone(Compound 1A-F)

To Compound (1A-E) (1.6 g, 5.78 mmols) were added acetone (15 ml),dimethoxypropane (1.81 g, 17.34 mmols) and p-toluenesulfonic acidmonohydrate (0.11 g, 0.578 mmols). The mixture was stirred at roomtemperature for 2 hours. After water (20 ml) and ethyl acetate (80 ml)were added to the reaction mixture, the pH of the aqueous phase wasadjusted to 7.0 with saturated hydrogensodium carbonate. Sodium chloridewas added to the aqueous phase for separation until it was saturated.The aqueous phase was further extracted twice with ethyl acetate (50ml). The ethyl acetate layers were collected and dried over anhydroussodium sulfate. The residue obtained after concentration was purified bysilica gel column chromatography (300 ml, hexane:ethyl acetate=3:1) togive Compound (1A-F) (1.6 g, yield: 87.4%).

1H-NMR (200 MHz, CDCl3) δ: 1.35 (1H, s), 1.42 (3H, s), 1.85-2.26 (5H,m), 2.30-2.85 (7H, m), 2.95-3.12 (1H, m), 3.70 (1H, dd, J=6.27 Hz, 8.22HZ), 3.98-4.32 (4H, m); MS (FAB, POS) m/z: 317 (M+H)+.

(6) Preparation of4-hydroxymethyl-2-[(2,3-O-isopropylidene)propylthio]methylcyclopentanone(Compound 1A-G)

To Compound (1A-F) (1.6 g, 5.05 mmols) were added methanol (20 ml) andwater (5 ml). Under ice cooling 1 N sodium hydroxide (3.2 ml, 3.20mmols) was added to the mixture followed by stirring for an hour. Afterthe pH was adjusted to 7.0 with 1 N hydrochloric acid, the reactionsolution was concentrated and saturated sodium chloride aqueous solution(15 ml) was added to the residue. After extracting 3 times with ethylacetate (30 ml), the ethyl acetate layer was dried over anhydrous sodiumsulfate and then concentrated to dryness. The residue was purified bysilica gel column chromatography (250 ml, ethyl acetate:hexane=2:1) togive Compound (1A-G) (1.0 g, yield: 72.4%).

1H-NMR (200 MHz, CDCl3) δ: 1.35 (3H, s), 1.42 (31H, s), 1.61-1.73 (1H,m), 1.95-2.85 (9H, m), 3.00 (1H, m), 3.60-3.78 (3H, m), 4.05-4.12 (1H,m), 4.18-4.33 (1, m); MS (FAB, POS) m/z: 275 (M+H)+.

(7) Preparation of4-hydroxymethyl-2-[(2,3-O-isopropylidene)propylsulfonyl]methylcyclopentanone(Compound 1A-H)

Compound (1A-G) (1.0 g, 3.64 mmols) was dissolved in dichloromethane (25ml). Under ice cooling, m-chloroperbenzoic acid (1.74 g, purity 80%,8.04 mmols) was added to the solution by 4 portions. After stirring for1.5 hours and filtering subsequently, water (10 ml), 20% sodium hydrogensulfite (1 ml) and saturated sodium hydrogen carbonate (2 ml) were addedto the filtrate. The mixture was stirred at room temperature for 15minutes. After saturated sodium chloride aqueous solution (20 ml) wasadded to the reaction solution, the mixture was separated. The aqueousphase was further extracted twice with dichloromethane (25 ml). Thedichloromethane layers were collected and dried over anhydrous sodiumsulfate and then concentrated. The residue was purified by silica gelcolumn chromatography (300 ml, ethyl acetate:hexane=3:1) to giveCompound (1A-H) (1.0 g, yield: 89.2%).

(8) Preparation of4-[(2,3-O-isopropylidene)propylsulfonyl]methyl-3-oxo-1-cyclopentanecarboxylicacid (Compound a)

Compound (1A-H) (1.0 g, 3.26 mmols) was dissolved in acetone (55 ml).While stirring, Jones reagent (2.5 ml) was dropwise added to thesolution over 15 minutes while chilling. The reaction solution wasstirred for 20 minutes, during which the reaction solution retainedorange color. 2-Propanol (1 ml) was added to the reaction mixture. Afterstirring for 5 minutes, the mixture was concentrated. To the residuewere added water (20 ml) and saturated sodium chloride aqueous solution(30 ml). The resulting mixture was extracted 8 times withdichloromethane (40 ml). The dichloromethane layer was washed withsaturated sodium chloride aqueous solution (200 ml), dried overanhydrous sodium sulfate and then concentrated. The residue was purifiedby silica gel column chromatography (100 ml, chloroform:methanol=10:1 to4 1) to give Compound (a) (0.69 g, yield: 66.3%).

1H-NMR (200 MHz, CDCl3) δ: 1.37 (3H, s), 1.44 (1.5H, s), 1.45 (1.5H, s),1.78-2.31 (1H, m), 2.32-3.51 (8H, m), 3.75 (2H, m), 4.20 (1H, dd, J=8.67Hz, 8.71 Hz), 4.60 (1H, m), 6.80 (1H, brs); MS (FAB, POS) m/z: 321(M+H)+.

(9) Preparation of4-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-3-oxo-1-cyclopentanecarboxylicacid (Compound 1A)

Compound (a) (170 mg, 0.53 mmols) was dissolved in acetone (7 ml). Tothe solution were added N-acetyl-L-cysteine (87 mg, 0.53 mmols) and 1 Nsodium hydroxide (1.5 ml). The mixture was stirred at room temperaturefor 2 hours. After the pH was adjusted to 6.8 by adding 1N hydrochloricacid to the reaction mixture, the mixture was concentrated. The residuewas purified on QAE-Sephadex (200 ml, C1 type, 0.05M-0.4 M sodiumchloride aqueous solution, 700 ml each, gradient elution) to obtain theobjective fraction. After the fraction was concentrated, methanol (3 ml)was added to filter insoluble salts off. The filtrate was purified bySephadex LH-20 (100 ml, 80% hydrated methanol) to give Compound (1A)sodium salt (85 mg, yield: 46.1%).

1H-NMR (200 MHz, CDCl3) δ: 108 (1H, m), 2.06 (3H, s), 2.10-2.80 (5H, m),2.81-3.16 (4H, m), 4.36 (1H, dd, J=44.4 Hz, 8.1 Hz); MS (FAB, POS) m/z:348 (M+H)+.

EXAMPLE 2 Preparation of4-[(2R)-(2-acetylamino-2-methoxycarbonyl)ethylthio]methyl-3-oxo-1-cyclopentanecarboxylicAcid (Compound 2A)

Acetone (6 ml), N-acetyl-L-cysteine methyl ester (110.6 mg, 0.624mmols), water (2 ml) and 1 N sodium hydroxide (1.25 ml) were added toCompound (a) (200 mg, 0.624 mmols). The mixture was stirred at roomtemperature for 2 hours. After the pH was adjusted to 6.8 by adding 1Nhydrochloric acid to the reaction mixture, the mixture was concentrated.The residue was purified on QAE-Sephadex (200 ml, C1 type, 0.05M-0.3 Msodium chloride aqueous solution, 700 ml each, gradient elution) toobtain the objective fraction. After the fraction was concentrated,methanol (3 ml) was added to filter insoluble salts off. The filtratewas purified by Sephadex LH-20 (100 ml, 80% hydrated methanol) to giveCompound (2A) sodium salt (140 mg, yield: 66.6%).

1H-NMR (200 MHz, CDCl3) δ: 1.80 (1H, m), 2.06 (3H, s), 2.08-2.80 (5H,m), 2.81-3.18 (4H, m), 3.79 (3H, s), 4.64 (1H, m); MS (FAB, POS) m/z:340 (M+H)+.

EXAMPLE 3 Preparation of(2RS,4S)-2-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-hydroxy-1-cyclopentanone(Compound 3A)

(1) Preparation of(4R)-2-[(2R)-(2-acetylamino-2-methoxycarbonyl)ethylthio]methyl-4-tert-butyldimethylsiloxy-2-cyclopenten-1-one(Compound 3A-b)

(4R)-2-(N,N-diethylamino)methyl-4-tert-butyldimethylsiloxy-2-cyclopenten-1-one(Compound 3A-a) (370 mg, 1.24 mmols) was dissolved in methanol (4 ml).To the solution was added iodomethane (0.16 ml, 2.48 mmols) followed bystirring at room temperature for 2 hours. After the reaction solutionwas concentrated, methanol (3 ml) and N-acetyl-L-cysteine methyl ester(220 mg, 1.24 mmols) were added to the residue. The mixture was stirredat room temperature for 1.5 hours. After the reaction solution wasconcentrated, the residue was purified by silica gel columnchromatography (60 ml, dichloromethane:methanol=40:1) to give Compound(3A-b) (378 mg, yield: 75.7%).

1H-NMR (200 MHz, CDCl3) δ: 0.12 (3H, s), 0.14 (3H, s), 0.92 (9H, s),2.07 (3H, s), 2.31 (1H, dd, J=2, 11 Hz, 18.31 Hz) 2.80 (1H, dd, J=5.99Hz, 18.31 Hz), 2.99 (2H, m), 3.30 (2H, m), 3.78 (3H, s), 4.86 (1H, m),4.92 (1H, m), 6.56 (1H, d, J=7.69 Hz), 7.29 (1H, m); MS (FAB, POS) m/z:402 (M+H)+.

(2) Preparation of(4R)-2-[(2R)-(2-acetylamino-2-methoxycarbonyl)ethylthio]methyl-4-hydroxy-2-cyclopenten-1-one(Compound 3A-c)

Methanol (4 ml), water (0.2 ml) and Dowex 50 (H+ type, 300 mg) wereadded to Compound (3A-b) (64 mg, 0.16 mmol). The mixture was stirred atroom temperature for 20 hours. The reaction mixture was concentrated andthe residue was purified by silica gel column chromatography (20 ml,dichloromethane:methanol=20:1) to give Compound (3A-c) (33.6 mg, yield:73.6%); MS (FAB, POS) m/z: 288 (M+H)+.

(3) Preparation of(4R)-2-[(2R)-(2-acetylamino-2-methoxycarbonyl)ethylsulfonyl]methyl-4-hydroxy-2-cyclopenten-1-one(Compound 3A-d)

Compound (3A-c) (33.6 mg, 0.117 mmol) was dissolved in dichloromethane(3 ml). Under ice cooling, m-chloroperbenzoic acid (purity 80%, 50 mg,0.23 mmol) was added to the solution. After stirring at room temperaturefor 2 hours, water (5 ml) and dichloromethane (5 ml) were added to thereaction mixture. Thereafter saturated sodium hydrogen carbonatesolution was added to the mixture until the aqueous layer becameneutral. Sodium hydrogen sulfite (20% aqueous solution, 5 drops) wasadded to the mixture for separation. After the dichloromethane layer wasconcentrated, the residue was purified by silica gel columnchromatography (20 ml, dichloromethane:methanol=10:1) to give Compound(3A-d) (36 mg, yield: 96.4%). MS (FAB, POS) m/z: 320 (M+H)+. (4)Preparation of(4S)-2-[(2R)-(2-acetylamino-2-methoxycarbonyl)ethylsulfonyl]methyl-4-hydroxycyclopentan-1-one (Compound c)

To Compound (3A-d) (36 mg, 0.112 mmol) were added ethanol (3 ml),methanol (1.5 ml) and 10% Pd—C (50% wet, 8.8 mg). The mixture wasstirred at room temperature for 10 hours in hydrogen atmosphere. Thereaction solution was filtered and the filtrate was concentrated to giveCompound (c) (36 mg, yield: 100%). MS (FAB, POS) m/z: 322 (M+H)+.

(5) Preparation of(2RS,4R)-2-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-hydroxy-1-cyclopentanone(Compound 3A)

Acetone (3 ml), N-acetyl-L-cysteine (24.3 mg, 0.149 mmols), methanol(1.5 ml) and 1 N sodium hydroxide (0.22 ml) were added to Compound (c)(48 mg, 0.149 mmols). The mixture was stirred at room temperature for1.5 hours. After silica gel (500 mg) was added to the reaction solution,the mixture was concentrated to dryness. The residue was purified bysilica gel column chromatography (80 ml, dichloromethane:methanol:aceticacid=5:1:0.1) and concentrated again. The residue was dissolved in water(4 ml). After adjusting the pH to 6.8 with 1N sodium hydroxide, thesolution was concentrated to give the sodium salt of Compound (3A) (26.6mg, yield: 60%).

1H-NMR (200 MHz, D2O) δ: 1.76 (1H, m), 2.00 (3H, s), 2.20 (1H, dd,J=7.13 Hz, 18.9 Hz), 2.30-3.16 (8H, m), 4.40-4.62 (2H, m); MS (ESI, NEG)m/z: 274 (M−H)−.

EXAMPLE 4(2RS,4S)-2-[(2R)-3-acetylamino-3-[1-{(2S)-methoxycarbonyl}pyrrolidinyl]-3-oxypropylthio]methyl-4-hydroxy-1-cyclopentanone(Compound 4A)

Compound (3) (28.2 mg, 0.1 mmol) and proline methyl ester hydrochloride(16.95 mg) were dissolved in dimethylformamide (3 ml). Under icecooling, triethylamine (14.1 ul), 1-hydroxy-benzotriazole (16.5 mg, 0.12mmol) and dicyclohexylcarbodiimide (23.1 mg) were added to the solution.The mixture was stirred at room temperature for 2 hours. The reactionsolution was concentrated and the residue was purified by silica gelcolumn chromatography (30 ml, dichloromethane:methanol=10:1) to giveCompound (4A) (18.2 mg, yield: 47%).

1H-NMR (200 MHz, CDCl3) δ: 1.85-2.10 (3H, m), 2.00 (3H, s), 2.10-3.13(10H, m), 3.64-3.90 (5H, m), 4.42-4.70 (2H, m), 4.98 (1H, m), 6.68 (1H,m); MS (FAB, POS) m/z: 387 (M+H)+.

EXAMPLE 52-((2R)-(2-acetylamino-2-methoxycarbonyl)ethylthio)methyl-3-oxo-1-indanecarboxylicAcid (Compound 6A)

After 37% formalin (0.088 ml, 1.08 mmol) was added to a mixture of3-oxo-1-indanecarboxylic acid (191 mg, 1.08 mmol) and piperidine (92.3mg, 1.08 mmol), the mixture was stirred at room temperature for 3 hours.The reaction solution was concentrated. Ethanol (3 ml) andN-acetyl-L-cysteine methyl ester (80 mg, 0.45 mmol) were added to theresidue. The mixture was heated to reflux for 10 minutes and thenconcentrated in vacuo. The residue was purified by silica gel columnchromatography (100 ml, chloroform:methanol:acetic acid=30:1:0.5) togive Compound (6A) (62 mg, yield: 15.7%).

1H-NMR (200 MHz, CDCl3) δ: 2.05-2.12 (3H), 2.63-3.30 (4H, m), 3.42 (1H,m), 3.74-3.81 (3H), 4.21 (1H, d, J=4.4 Hz), 4.89 (1H, m), 6.66-6.80 (1H,NH), 7.25 (1H, brs), 7.41-7.86 (4H, m); MS (FAB, POS) m/z: 366 (M+H)+.

EXAMPLE 6(1R,2S)-2-[(2R)-{2-acetylamino-3-oxo-3-(1-pyrrolidinyl)}propylthio]methyl-3-oxo-1-cyclopentanecarboxylicAcid (Compound 1B)

(1)(2S,3R)-3-acetoxymethyl-2-[(2RS)-2,3-bis(hydroxy)propylthio]methylcyclopentanone(Compound A-2)

Alpha-thioglycerin (9.558 g, 90.17 mmols) was added to a solution of(2R,3R)-2,3-bis(acetoxymethyl)cyclopentanone (Compound A) (20.56 g,90.17 mmols) in acetone (178 ml). Then methanol (20 ml) and 1 N sodiumhydroxide (90.17 ml) were added to the mixture followed by stirring atroom temperature for 40 minutes. After the pH was adjusted to 7.0 byadding 1 N hydrochloric acid to the reaction solution, the mixture wasconcentrated. The residue obtained was dissolved in methanol (200 ml)and silica gel (120 g) was added to the solution. The mixture wasconcentrated to dryness, which was then purified by silica gel columnchromatography (330 ml, dichloromethane:methanol=25:1 to 5:1) to giveCompound (A-2) (22.06 g, yield: 88.63%).

1H-NMR (200 MHz, CD3OD) δ: 1.56-1.79 (1H, m), 2.07 (3H, s), 2.07 (3H,s), 2.10-2.16 (9H, m), 3.50-3.60 (2H, m), 3.66-3.78 (1H, m), 4.21-4.34(2H, m); MS (FAB, POS) m/z: 277 (M+H)+.

(2) Preparation of(2S,3R)-3-acetoxymethyl-2-[(2RS)-(2,3-O-isopropylidene)propylthio]methylcyclopentanone(Compound A-3)

Compound (A-2) (22.06 g, 79.92 mmols) was dissolved in anhydrous acetone(120 ml). Under ice cooling, p-toluenesulfonic acid monohydrate (1.5 g),dimethoxypropane (29.46 ml, 240 mmols) were added to the solution. Themixture was stirred at room temperature for 30 minutes. After water (150ml) and ethyl acetate (300 ml) were added to the reaction mixture, thepH of the aqueous phase was adjusted to 7.0 with saturated sodiumhydrogen carbonate. The aqueous phase was extracted twice with ethylacetate (300 ml). The ethyl acetate layer was washed with saturatedsodium chloride aqueous solution (160 ml), dried over anhydrous sodiumsulfate and concentrated in vacuo to give Compound (A-3) (24.00 g,yield: 95.0%).

1H-NMR (200 MHz, CDCl3) δ: 1.35 (3H, s), 1.42 (3H, s), 1.51-1.76 (1H,m), 2.08 (3H, s), 2.10-2.96 (9H, m), 3.65-3.74 (1H, m), 4.05-4.18 (1H,m), 4.18-4.29 (2H, m); MS (FAB, POS) m/z: 317 (M+H)+.

(3) Preparation of(2S,3R)-3-hydroxymethyl-2-[(2RS)-(2,3-O-isopropylidene)propylthio]methylcyclopentanone(Compound A-4)

Compound (A-3) (25.22 g, 79.81 mmols) was dissolved in methanol (253ml). Under ice cooling, 1N sodium hydroxide (50 ml) was added to thesolution. The mixture was stirred at room temperature for 18 minutes.After the pH of the mixture was adjusted to 5.8 with 1N hydrochloricacid while ice cooling, the mixture was concentrated in vacuo to givethe residue. Water (50 ml) was added to the residue and the mixture wasextracted 3 times with ethyl acetate (200 ml). The ethyl acetate layerwas washed with saturated sodium chloride aqueous solution (100 ml),dried over anhydrous sodium sulfate and concentrated in vacuo. The thusobtained residue was purified by silica gel column chromatography (300ml, dichloromethane:methanol=30:1) to give Compound (A-4) (18.67 g,yield: 85.3%).

1H-NMR (200 MHz, CDCl3) δ: 1.36 (3H, s), 1.43 (3H, s), 1.58-1.81 (1H,m), 2.00-2.82 (9H, m), 3.02-3.11 (1H, dd, J=3.6 Hz, 13.2 Hz), 3.64-3.73(1H, m), 3.76-3.91 (2H, m), 4.06-4.34 (2H, m); MS (FAB, POS) m/z: 275(M+H)+.

(4) Preparation of(2S,3R)-3-hydroxymethyl-2-[(2RS)-(2,3-O-isopropylidene)propylsulfonyl]methylcyclopentanone(Compound A-5)

Compound (A-4) (5.558 g, 20.28 mmol) was dissolved in dichloromethane(55 ml). Under ice cooling, a solution of m-chloroperbenzoic acid(purity 80%, 8.74 g, 40.56 mmols) in dichloromethane (85 ml) was addedto the solution. The mixture was stirred at room temperature for anhour. The reaction solution was filtered and to the filtrate, 20% sodiumhydrogen sulfite (6.48 ml), saturated sodium carbonate aqueous solution(16.2 ml) and further water (50 ml) were added followed by stirring for10 minutes. After liquid-liquid separation, the dichloromethane layerwas washed with saturated sodium chloride aqueous solution (100 ml),dried over anhydrous sodium sulfate and concentrated in vacuo. The thusobtained residue was purified by silica gel column chromatography (150ml, hexane:ethyl acetate=1:3) to give Compound (A-5) (5.798 g, yield:93.4%).

1H-NMR (200 MHz, CDCl3) δ: 1.38 (3H, s), 1.45 (3H, s), 1.68-1.92 (1H,m), 1.99-2.76 (6H, m), 3.10-3.50 (3H, m), 3.70-4.08 (4H, m), 4.10-4.24(1H, dd, J=6.14 Hz, 7.42 Hz), 4.56-4.68 (1H, m); MS (FAB, POS) m/z: 307(M+H)+.

(5) Preparation of(1R,2S)-2-[(2RS)-(2,3-O-isopropylidene)propylsulfonyl]methyl-3-oxo-1-cyclopentanecarboxylicacid (Compound C)

Compound (A-5) (5.80 g, 18.94 mmols) was dissolved in acetone (320 ml).While stirring Jones reagent was added to the solution until thereaction solution maintained its orange color. Under ice cooling,2-propanol was added to the reaction mixture until the reaction solutionturned green. The mixture was concentrated in vacuo to remove acetone.To the residue water (120 ml) was added. The mixture was extracted twicewith dichloromethane (200 ml). The dichloromethane layer was washed withsaturated sodium chloride aqueous solution (80 ml), dried over anhydroussodium sulfate and then concentrated in vacuo to give Compound (C) (4.59g, yield: 75.7%).

1H-NMR (200 MHz, CDCl3) δ: 1.37 (3H, s), 1.43 (1.5H, s), 1.47 (1.5H, s),2.02 (1H, m), 2.22-2.65 (3H, m), 2.94-3.32 (3H, m), 3.32-3.84 (4H, m),4.19 (1H, m), 4.40 (1H, m), 4.59 (1H, m); MS (ESI, NEG) m/z: 319 (M−H)−.

(6) Preparation of(1R,2S)-2-[(2R)-{2-acetylamino-3-oxo-3-(1-pyrrolidinyl}propylthio]methyl-3-oxo-1-cyclopentanecarboxylicacid (Compound 1B)

Compound (C) (32 mg, 0.1 mmol) was dissolved in acetone (2 ml) and, asolution of (2R)-2-acetylamino-3-oxo-3-(1-pyrrolidinyl)propanethiol(21.6 mg, 0.1 mmol) in acetone (1 ml) was added thereto. The mixture wasstirred at room temperature for 2 hours. After 1N hydrochloric acid wasadded to the reaction solution to adjust the pH to 6.8, the mixture wasconcentrated. The residue was purified on QAE-Sephadex (C1 type, 110 ml,0.05M-0.5M NaCl, 300 ml each, gradient elution). The objective fractionswere collected. After the pH was adjusted to 2.6, the product wasadsorbed onto DIAION-SP207 (10 ml, Nippon Rensui K.K.), then washed withwater and eluted with 80% hydrated methanol. After the pH was adjustedto 6.8 with 1N sodium hydroxide, the eluate was concentrated to drynessto give Compound (1B) sodium salt (26 mg, yield: 68.7%).

1H-NMR (200 MHz, D2O) δ: 1.75-2.05 (5H, m), 1.98 (3H, s), 2.06-2.61 (3H,m), 2.62-3.25 (6H, m), 3.28-3.49 (2H, m), 3.52-3.75 (2H, m), 4.69 (1H,t, J=6.88 Hz); MS (ESI, NEG) m/z: 355 (M−Na)−.

EXAMPLE 7 Preparation of(1R,2S)-2-[(2R)-{2-acetylamino-3-(4-morpholinyl)-3-oxo}propylthio]methyl-3-oxo-1-cyclopentanecarboxylicAcid (Compound 2B)

Compound (C) (32 mg, 0.1 mmol) was dissolved in acetone (2 ml) and, asolution of (2R)-2-acetylamino-3-(4-morpholinyl)-3-oxopropanethiol (23.2mg, 0.1 mmol) in acetone (1 ml) was added thereto. The mixture wasstirred at room temperature for 1.5 hours. Purification was made in amanner similar to Example 1 to give Compound (2B) sodium salt (22.4 mg,yield: 56.8%).

1H-NMR (200 MHz, D2O) δ: 1.78-1.98 (1H, m), 1.99 (1H, s), 2.05-2.60 (3H,m), 2.65-3.00 (6H, m), 3.45-3.89 (8H, m), 4.90 (1H, t, J=6.96); MS (FAB,POS) m/z: 395 (M+Na+H)+.

EXAMPLE 8 Preparation of(1R,2S)-2-[(2R)-12-acetylamino-3-oxo-3-(1-piperidinyl)propylthiol1methyl-3-oxo-1-cyclopentanecarboxylicAcid Compound 3B)

Compound (C) (32 mg, 0.1 mmol) was dissolved in acetone (2 ml). Asolution of (2R)-2-acetylamino-3-(1-piperidinyl)-3-oxopropanethiol (23mg, 0.1 mmol) in acetone (1 ml) and 1N sodium hydroxide (0.2 ml) wereadded to the solution. The mixture was stirred at room temperature for1.5 hours. Purification was made in a manner similar to Example 6 togive the sodium salt (26.0 mg, yield: 66.3%) of Compound (3B).

1H-NMR (200 MHz, D2O) δ: 1.40-1.72 (6H, m), 1.82 (1H, m), 1.98 (3H, s),2.04-2.60 (3H, m), 2.62-3.20 (4H, m), 3.32-3.70 (4H, m), 4.98 (1H, t,J=7.04 Hz); MS (ESI, NEG) m/z: 369 (M−Na)−.

EXAMPLE 9 Preparation of(1R,2S)-2-[(2R)-({2-carboxy-2-pentafluoropropionylaminoethylthio]methyl-3-oxo-1-cyclopentanecarboxylic Acid (Compound 4B)

Compound (C) (32 mg, 0.1 mmol) was dissolved in acetone (2 ml). Asolution of (2R)-2-carboxy-2-pentafluoropripionylaminoethanethiol (25.3mg, 0.1 mmol) in acetone (1 ml), methanol (1 ml) and 1N sodium hydroxide(0.3 ml) were added to the solution. The mixture was stirred at roomtemperature for 1.5 hours. Purification was made in a manner similar toExample 1 to give the sodium salt (30.0 mg, yield: 66.5%) of Compound(4B).

1H-NMR (200 MHz, D2O) δ: 1.71-1.98 (1H, m), 2.05-2.60 (3H, m), 2.62-3.25(6H, m), 4.41 (1H, dd, J=4.19 Hz, 9.24 Hz); MS (ESI, NEG) m/z: 428(M−Na)−.

EXAMPLE 10 Preparation of trans-2-[(2R)-{2-acetylamino-3-oxo-3-(1-pyrrolidinyl)}propylthio]methyl-3-methoxycarbonyl-1-cyclopentanone(Compound 5B)

(1) Preparation oftrans-3-acetoxy-2-[2,3-bis(hydroxy)propylthio]methylcyclopentanone(Compound a-2)

A solution of trans-2,3-bis(acetoxymethyl)cyclopentanone (Compound (a),18.72 g, 81.8 mmols) in acetone (160 ml) was added to alpha-thioglycerin(8.7 g). The mixture was stirred at room temperature for 20 minutes. Thereaction solution was concentrated. The residue obtained was dissolvedin methanol and silica gel (100 g) was added thereto followed byconcentration. The residue was purified by silica gel columnchromatography (300 ml, dichloromethane:methanol=20:1 to 5:1) to giveCompound (a-2) (21.88 g, yield: 96.8%).

1H-NMR (200 MHz, CD3OD) δ: 1.56-1.79 (1H, m), 2.07 (3H, s), 2.10-2.96(9H, m), 3.56-3.60 (2H, m), 3.66-3.78 (1H, m), 4.21-4.34 (2H, m); MS(FAB, POS) m/z: 277 (M+H)+.

(2) Preparation oftrans-3-acetoxy-2-[2,3-O-isopropylidene)propylthio]methylcyclopentanone(Compound a-3)

Compound (a-2) (21.9 g, 79.27 mmols) was dissolved in anhydrous acetone(120 ml). Under ice cooling, p-toluenesulfonic acid monohydrate (1.4 g),dimethoxypropane (29.4 ml) were added to the solution. The mixture wasstirred at room temperature for 30 minutes. After water (140 ml) andethyl acetate (280 ml) were added to the reaction mixture, the pH of theaqueous phase was adjusted to 7.0 with saturated sodium hydrogencarbonate. The aqueous phase was extracted twice with ethyl acetate (280ml). The ethyl acetate layer was washed with saturated sodium chlorideaqueous solution (150 ml), dried over anhydrous sodium sulfate andconcentrated to give Compound (a-3) (23.34 g, yield: 93.2%).

1H-NMR (200 MHz, CDCl3) δ: 1.35 (3H, 1.42 (3H, s), 1.50-1.76 (1H, m),2.08 (3H, m), 2.10-2.96 (9H, m), 3.65-3.74 (1H, m), 4.05-4.18 (2H, m),4.18-4.29 (2H, m); MS (FAB, POS) m/z: 317 (M+H)+.

(3) Preparation oftrans-3-hydroxymethyl-2-[2,3-O-isopropylidene)propylthio]methylcyclopentanone(Compound a-4)

Compound (a-3) (1097 mg, 3.47 mmols) was dissolved in methanol (200 ml)and under ice cooling, 1 N sodium hydroxide (3.47 ml) was added to thesolution. The mixture was stirred at room temperature for 15 minutes.After the pH was adjusted to 7.0 with 1N hydrochloric acid while icecooling, the mixture was concentrated. Water (3 ml) was added to theresidue obtained followed by extracting 3 times with ethyl acetate (15ml). The ethyl acetate layer was washed with saturated sodium chlorideaqueous solution (10 ml), dried over anhydrous sodium sulfate and thenconcentrated. The obtained residue was purified by silica gel columnchromatography (50 ml, chloroform methanol=30:1) to give Compound (a-4)(739 mg, yield: 77.5%).

1H-NMR (200 MHz, CDCl3) δ: 1.35 (3H, s), 1.43 (3H, s), 1.58-1.81 (1H,m), 2.00-2.81 (9H, m), 3.02-3.11 (1H, dd, J=3.5 Hz, 13.2 Hz), 3.64-3.73(1H, m), 3.76-3.91 (2H, m), 4.06-4.34 (1H, m); MS (FAB, POS) m/z: 275(M+H)+.

(4) Preparation of trans-3-hydroxymethyl-2-[2,3-O-isopropylidenepropylsulfonyl 1methylcyclopenta none (Compound a-5)

Compound (a-4) (5140 mg, 18.76 mmol) was dissolved in dichloromethane(50 ml). Under ice cooling, a solution of m-chloroperbenzoic acid (8093mg, purity 80%, 37.32 mmols) in dichloromethane (80 ml) was added to thesolution. The mixture was stirred at room temperature for 2 hours. Thereaction solution was filtered and to the filtrate, 20% sodium hydrogensulfite (6 ml), saturated sodium carbonate aqueous solution (6 ml) andfurther water (50 ml) were added followed by stirring. Afterliquid-liquid separation, the dichloromethane layer was washed withsaturated sodium chloride aqueous solution (30 ml), dried over anhydroussodium sulfate and concentrated. The thus obtained residue was purifiedby silica gel column chromatography (160 ml, hexane:ethyl acetate=1:3)to give Compound (a-5) (4610 mg, yield: 80.3%).

1H-NMR (200 MHz, CDCl3) δ: 1.37 (3H, s), 1.46 (3H, s), 1.73-1.92 (1H,m), 1.98-2.73 (6H, m), 3.10-3.49 (3H, m), 3.68-4.08 (4H, m), 4.16-4.24(1H, dd, J=6.14 Hz, 7.42 Hz), 4.56-4.68 (1H, m); MS (FAB, POS) m/z: 307(M+H)+.

(5) Preparation oftrans-2-[(2,3-O-isopropylidenelpropylsulfonyl]methyl-3-oxo-1-cyclopentanecarboxylicacid (Compound c]

Compound (a-5) (2630 mg, 8.59 mmols) was dissolved in acetone (150 ml).While stirring Jones reagent was added to the solution until thereaction solution turned orange. Under ice cooling, 2-propanol was addedto the reaction mixture until the reaction solution turned green. Themixture was concentrated and water (60 ml) was added to the residue. Themixture was extracted 3 times with dichloromethane (100 ml). Thedichloromethane layer was washed with saturated sodium chloride aqueoussolution (40 ml), dried over anhydrous sodium sulfate and thenconcentrated to give Compound (c) (1948 mg, yield: 70.8%).

1H-NMR (200 MHz, CDCl3) δ: 1.37 (3H, s), 1.43 (1.5H, s), 1.47 (1.5H, s),2.02 (1H, m), 2.22-2.65 (3H, m), 2.94-3.32 (3H, m), 3.32-3.84 (4H, m),4.19 (1H, m), 4.40 (1H, m), 4.59 (1H, m); MS (ESI, NEG) m/z: 319 (M−H)−.

(6) Preparation oftrans-2-[(2R)-{2-acetylamino-3-oxo-3-(1-pyrrolidinyl)}propylthio]methyl-3-methoxycarbonyl-1-cyclopentanone(Compound 5B)

Compound (c) (32 mg, 0.1 mmol),(2R)-2-acetylamino-3-oxo-3-(1-pyrrolidinyl)propanethiol (21.6 mg, 0.1mmol) and 1N sodium hydroxide (0.2 ml) are reacted and purified in amanner similar to Example 1 to give sodiumtrans-2-[(2R)-{2-acetylamino-3-oxo-3-(1-pyrrolidinyl)}ethylthio]methyl-3-oxo-1-cyclopentanecarboxylate.The product was dissolved in DMF (3 ml) and methyl iodide (20 ul) wasadded thereto followed by stirring at room temperature for 35 minutes.The reaction solution was concentrated to dryness. The residue waspurified by silica gel column chromatography (20 ml,dichloromethane:methanol=25:1) to give Compound (5B) (18 mg, yield:48.6%).

1H-NMR (200 MHz, CDCl3) δ: 1.80-2.10 (5H, m), 2.00 (3H, s), 2.10-2.60(3H, m), 2.68-3.20 (6H, m), 3.38-3.70 (4H, m), 3.75 (3H, s), 4.90 (1H,m), 6.58 (1H, d, J=8.34 Hz); MS (FAB, POS) m/z: 371 (M+H)+.

EXAMPLE 11 Preparation oftrans-2-[(2R)-[2-acetylamino-3-{1-((2S)-2-methoxycarbonylpyrrolidinyl)}-3-oxo]propylthio]methyl-3-oxo-1-cyclopentanecarboxylicAcid (Compound 6B)

Compound (c) (53 mg, 0.165 mmol) and(2R)-2-acetylamino-3-[1-{(2S)-2-methoxycarbonyl]pyrrolidinyl}-3-oxopropanethiol(45.3 mg, 0.165 mmol) were dissolved in acetone (3 ml). Methanol (1 ml)and 1N sodium hydroxide (0.33 ml) were added to the solution. Themixture was stirred at room temperature for 1.5 hours. After 1Nhydrochloric acid was added to the reaction mixture to adjust the pH to2.5, the mixture was concentrated to dryness. The residue was purifiedby silica gel column chromatography (25 ml,dichloromethane:methanol=10:1) to give Compound (6B) (40.3 mg, yield:58.9%).

1H-NMR (200 MHz, CDCl3) δ: 1.80-2.55 (8H, m), 2.01-2.02 (3H, sx2),2.56-3.42 (6H, m), 3.62-4.00 (5H, m), 4.50 (1H, m), 4.75-5.19 (1H, m),7,207.52 (1H, m), 7.80 (1H, brs); MS (ESI, NEG) m/z: 414 (M−H)−.

EXAMPLE 12 Preparation oftrans-2-[(2R)-[2-acetylamino-3-{1-((2S)-2-methoxycarbonylazetidinyl)}-3-oxo]propylthio]methyl-3-oxo-1-cyclopentanecarboxylicAcid (Compound 7B)

Compound (c) (92 mg, 0.288 mmol) and(2R)-2-acetylamino-3-[1-{(2S)-2-methoxycarbonyl]azetidinyl}-3-oxopropanethiol(75.0 mg, 0.288 mmol) were dissolved in acetone (3 ml). Methanol (1 ml)and 1N sodium hydroxide (0.58 ml) were added to the solution. Themixture was stirred at room temperature for 1.5 hours. After 1Nhydrochloric acid was added to the reaction mixture to adjust the pH to2.5, the mixture was concentrated to dryness. The residue was purifiedby silica gel column chromatography (25 ml,dichloromethane:methanol=10:1) to give Compound (7B) (43.0 mg, yield:373 mg).

1H-NMR (200 MHz, CDCl3) δ: 2.00 (3H, sx2), 2.08-3.60 (12H, m), 3.76-3.84(3H, sx2), 3.99-4.55 (2H, m), 4.60-5.35 (2H, m), 7.12-7.50 (1H, m),7.90-8.60 (1H, brs); MS (ESI, NEG) m/z: 399 (M−H)−.

EXAMPLE 13 Preparation oftrans-2-[(2R)-(2-carboxy-2-pentafluoropropionylaminoethylthio]methyl-3-hydroxymethyl-1-cyclopentanone (Compound 8B)

Compound (c) (45.6 mg, 0.2 mmol) was dissolved in acetone (4 ml).(2R)-2-carboxyl-2-pentafluoro-propionylaminoethanethiol (50.6 mg, 0.2mmol) in methanol (1.5 ml) and 1N sodium hydroxide (0.8 ml) were addedto the solution. The mixture was stirred at room temperature for anhour. After 1N hydrochloric acid was added to the reaction mixture toadjust the pH to 2.5, the mixture was concentrated to dryness. Theresidue was purified in a manner similar to Example 1 to give Compound(8B) (71 mg, yield: 83.1%).

1H-NMR (200 MHz, D2O) δ: 1.50-1.76 (1H, m), 2.20-2.65 (5H, m), 2.70-3.00(3H, m), 3.50-3.90 (2H, m), 4.43 (1H, m); MS (FAB, POS) m/z: 416 (M+H)+.

EXAMPLE 14 Preparation of trans-2-[(11-acetylamino-11-carboxyundecylthio]methyl-3-oxo-1-cyclopentanecarboxylic Acid (Compound 9B)

(1) Preparation of1-acetylamino-11-benzyloxy-1,1-diethoxycarbonylundecane (Compound r-2)

Anhydrous ethanol (10.5 ml) and diethylacetamide malonate (2661 mg,12.25 mmols) were added to sodium ethoxide (834 mg, 12.25 mmols). Afterstirring for 10 minutes, 1-benzyloxy-10-iododecane (Compound q-1) (2661mg, 12.25 mmols) was added to the mixture. The mixture was heated toreflux for 4 hours and concentrated in vacuo. Chloroform (200 ml) andwater (100 ml) were added to the residue for separation. The organiclayer was washed with saturated sodium chloride aqueous solution (100ml), dried over anhydrous sodium sulfate and then concentrated. Theresidue was purified by silica gel column chromatography (300 ml,hexane:ethyl acetate=4:1) to give Compound (r-2) (5080 mg, yield:89.7%).

1H-NMR (200 MHz, CDCl3) δ: 1.05-1.42 (18H, m), 1.60 (4H, m), 2.02 (3H,s), 2.30 (2H, m), 3.48 (2H, t, J=6.64 Hz), 4.26 (4H, q, J=7.08 Hz), 4.50(2H, s), 6.78 (1H, brs), 7.30 (5H, m)

(2) Preparation of1-acetylamino-1,1-diethoxy-carbonyl-11-hydroxyundecane (Compound r-3)

Compound (r-2) (5090 mg, 10.99 mmols) was dissolved in ethanol (132 ml)and 10% Pd—C (50% wet, 1100 mg) was added to the solution. The mixturewas stirred at room temperature for 3 hours in hydrogen atmosphere. Thereaction solution was filtered and the filtrate was concentrated to giveCompound (r-3) (3760 mg, yield: 91.7%).

MS (FAB, POS) m/z: 374 (M+H)+.

(3) Preparation of 1-acetylamino-1-carboxy-11-hydroxyundecane (Compoundr-4)

Compound (r-3) (3760 mg, 10.08 mmols) was dissolved in ethanol (6 ml).After the pH was adjusted to 2.0 with 1N hydrochloric acid, the mixturewas heated to reflux for 8 hours, during which the pH was maintained at2.0 by adding 1N hydrochloric acid. The reaction solution was cooled toprecipitate colorless crystals. The crystals were filtered to giveCompound (r-4) (1341 mg, yield: 48.7%).

MS (FAB, POS) m/z: 274 (M+H)+.

(4) Preparation of 1-acetylamino-11-acetylthio-1-methoxycarbonylundecane(Compound r-5)

Compound (r-4) (176 mg, 0.64 mmol) was dissolved in methanol (2 ml) andTMS-diazomethane was added thereto. After reacting them for 15 minutes,the mixture was concentrated. The residue was added to a solution of2-fluoro-1-methylpyridinium p-toluenesulfonate (190 mg, 0.637 mmol) inbenzene acetone (1:1, 3 ml), and triethylamine (88.6 ul) was furtheradded thereto. The mixture was stirred at 30° C. for 2 hours. Thioaceticacid (45.5 ul) and triethylamine (88.6 ul) were added to the reactionsolution. The mixture was heated to reflux for 2 hours. After thereaction solution was concentrated, dichloromethane (10 ml) and water (5ml) were added to the residue for liquid separation. The aqueous layerwas extracted twice with dichloromethane (10 ml). The dichloromethanelayers were collected, dried over anhydrous sodium sulfate and thenconcentrated. The obtained residue was purified by silica gel columnchromatography (25 ml, dichloromethane) to give Compound (r-5) (222 mg,yield: 100%).

1H-NMR (200 MHz, CDCl3) δ: 1.30 (15H, m), 1.47-1.96 (5H, m), 2.04 (3H,s), 2.33 (3H, s), 2.89 (2H, t, J=7.04 Hz), 3.76 (3H, s), 4.61 (1H, m),6.02 (1H, d, J=7.69 Hz)

(5) Preparation of 1-acetylamino-1-carboxy-11-mercaptoundecane (Compoundr)

Compound (r-5) (222 mg, 0.64 mmol) was dissolved in methanol (3 ml) and1N hydrochloric acid (1.3 ml) was added to the solution followed bystirring at room temperature for 2 hours. After the pH was adjusted to3.0 with 1N hydrochloric acid, the mixture was concentrated. The residueobtained was purified by silica gel column chromatography (20 ml,dichloromethane:methanol=15:1) to give Compound (r) (123 mg, yield:66.9%).

MS (ESI, NEG) m/z: 288 (M−H)−.

(6) Preparation oftrans-2-[(11-acetylamino-11-carboxy)undecylthio]methyl-3-oxo-1-cyclopentanecarboxylicacid (Compound 9B)

Compound (r) (57.8 mg, 0.2 mmol) andtrans-2-[(2RS)-(2,3-O-isopropylidene)propylsulfonyl]methyl-3-oxo-1-cyclopentanecarboxylicacid (Compound c) (64 mg, 0.2 mmol) were dissolved in acetone (3 ml).After 1N sodium hydroxide (0.6 ml) was added to the solution, themixture was stirred at room temperature for 1.5 hours. The pH was thenadjusted to 6.8 with 1N hydrochloric acid. The mixture was concentratedand the residue obtained was purified by QAE-Sephadex. The pH was againadjusted to 6.8. The product was adsorbed to activated carbon (12 ml),washed with water and eluted with 80% hydrated methanol. The eluate wasconcentrated to give the sodium salt of Compound (9B) (28.9 mg, yield:32.7%).

1H-NMR (200 MHz) δ: 1.15-1.41 (16H, m), 1.45-1.98 (5H, m), 1.99 (3H, s),2.10-2.65 (5H, m), 2.71-3.00 (4H, m), 4.08 (1H, dd, J=4.68, 8.6 Hz); MS(ESI, NEG) m/z: 450 (M−Na)−.

EXAMPLE 15 Preparation of(1R,2S)-2-[(2R)-2-acetylamino-3-oxo-3-{1-(4-phenyl)piperazinyl}propylthio]methyl-3-oxo-1-cyclopentanecarboxylicAcid (Compound 13B]

A methanol solution (3 ml) of(2R)-2-acetylamino-3-oxo-3-[1-(4-phenylpiperazinyl)]-propanethiol (29.3mg, 1 mmol), acetone (1 ml) and 1N sodium hydroxide (0.2 ml) were addedto Compound (C) (32 mg, 1 mmol). The mixture was stirred at roomtemperature for 3 hours. After the pH was adjusted to 2.8 by adding 1Nhydrochloric acid was to the reaction solution, silica gel (200 mg) wasadded thereto. The mixture was concentrated to dryness. The residue waspurified by silica gel column chromatography (30 ml,chloroform:methanol=10:1) to give Compound (13B) (28.5 mg, yield:63.7%).

1H-NMR (200 MHz, CDCl3) δ: 1.85, 2.13 (1H, m), 2.01 (3H, s), 2.06-2.60(3H, m), 2.63-3.12 (6H, m), 3.68-3.92 (4H, m), 5.25 (1H, dd, J=6.96 Hz,15.02 Hz), 6.25 (1H, brs), 6.93 (3H, m), 7.28 (2H, m), 7.48 (1H, d,J=8.42 Hz); MS (FAB, POS) m/z: 448 (M+H)+.

EXAMPLE 16 Preparation of(1R,2S)-2-{3-(3-pyridyl)propylthio}-methyl-3-oxo-1-cyclopentanecarboxylicAcid (Compound 14B)

Compound (C) (32 mg, 0.1 mmol) was dissolved in acetone (1 ml) and, amethanol solution (1 ml) of 3-(3-pyridyl)propanethiol (15.3 mg, 0.1mmol) and 1N sodium hydroxide (0.18 ml) were added thereto. The mixturewas stirred at room temperature for 3 hours. The mixture wasconcentrated and the residue was purified on QAE-Sephadex (C1 type, 110ml, 0.05M-0.5M sodium chloride aqueous solution, 300 ml each, gradientelution). The objective fractions were collected. After the pH wasadjusted to 2.8, the product was adsorbed onto SEPABEADS SP207 (12 ml,Nippon Rensui K.K.), washed with water and eluted with 80% hydratedmethanol. By collecting the objective fractions, Compound (14B) (29.6mg, yield: 89.8%) was obtained.

1H-NMR (200 MHz, CD3OD) δ: 1.81-2.08 (3H, m), 2.10-2.60 (5H, m),2.68-3.00 (5H, m), 3.08 (1H, m), 7.40 (1H, m), 7.78 (1H, m), 8.40 (2H,m); MS (FAB, POS) m/z: 294 (M+H)+.

EXAMPLE 17 Preparation of (1R,2S)-2-[3-{3-(1-methylpyridiniumiodide)}propylthio]methyl-3-oxo-1-cyclopentanecarboxylic Acid (Compound15B)

Compound (C) (32 mg, 0.1 mmol) was dissolved in acetone (1 ml). Amethanol solution (1.5 ml) of 3-{3-(1-methylpyridiniumiodide)}propanethiol (30 mg, 0.1 mmol) and 1N sodium hydroxide are addedto the solution. The mixture was stirred at room temperature for 2hours. After the reaction solution was concentrated, the residue waspurified in a manner similar to Example 16 to give Compound (15B) (17.8mg, yield: 41%).

1H-NMR (200 MHz, CD3OD) δ: 1.85-2.10 (3H, m), 2.12-2.48 (3H, m),2.48-2.86 (5H, m), 2.87-3.08 (3H, m), 4.42 (3H, m), 7.99 (1H, dd, J=6.23Hz, 7.69 Hz), 8.48 (1H, d, J=7.69 Hz), 8.76 (1H, d, J=6.23 Hz), 8.89(2H, m); MS (FAB, POS) m/z: 308 (M−H)+.

EXAMPLE 18 Preparation of5-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-2-cyclopenten-1-one(Compound 1C)

(1) Preparation of(4R)-2-[(2R)-(2-acetylamino-2-methoxycarbonyl)ethylthio]methyl-4-tert-butyldimethylsiloxy-2-cyclopenten-1-one(Compound a)

Compound (c) (370 mg, 1.24 mmols) was dissolved in methanol (4 ml) andmethyl iodide (0.16 ml, 2.48 mmols) was added to the solution. Themixture was stirred at room temperature for 2 hours. After the reactionsolution was concentrated, methanol (3 ml) and N-acetyl-L-cysteinemethyl ester (220 mg, 1.24 mmol) were added to the residue. The mixturewas stirred at room temperature for 1.5 hrs. The reaction solution wasconcentrated and the residue was purified by silica gel columnchromatography (60 ml, dichloromethane:methanol=40:1) to give Compound(a-1) (378 mg, yield: 75.7%).

1H-NMR (200 MHz, CDCl3) δ: 0.12 (3H, s), 0.14 (3H, s), 0.92 (9H, s),2.07 (3H, s), 2.31 (1H, dd, J=2.11 Hz, 18.31 Hz), 2.80 (1H, dd, J=5.99Hz, 18.31 Hz), 2.99 (2H, m), 3.30 (2H, m), 3.78 (3H, s), 4.86 (1H, m),4.92 (1H, m), 6.56 (1H, d, J=7.69 Hz), 7.29 (1H, m); MS (FAB, POS) m/z:402 (M+H)+.

(2) Preparation of(4R)-2-[(2R)-(2-acetylamino-2-methoxycarbonyl)ethylsulfonyl]methyl-4-tert-butyldimethylsiloxy-2-cyclopenten-1-one(Compound a-2)

Compound (a-1) (378 mg, 0.94 mmol) was dissolved in dichloromethane (30ml). Under ice cooling, m-chloroperbenzoic acid (406 mg, purity 80%,1.88 mmol) was added to the solution. After water (15 ml) and 20% sodiumhydrogen sulfite (3 ml) were added to the reaction solution, saturatedsodium hydrogen carbonate was added to the mixture until the pH of theaqueous layer became 7.0. The dichloromethane layer was washed withsaturated sodium chloride aqueous solution and concentrated. The residuewas purified by silica gel column chromatography (50 ml,dichloromethane:methanol=10:1) to give Compound (a-2) (355 mg, yield:87.3%).

1H-NMR (200 MHz, CDCl3) δ: 0.13 (3H, s), 0.14 (3H, s), 0.96 (9H, s),2.08 (3H, s), 2.35 (1H, dd, J=2.16 Hz, 18.52 Hz), 2.86 (1H, dd, J=5.94Hz, 18.52 Hz), 3.65 (2H, d, J=4.97 Hz), 3.80 (3H, s), 3.81-4.16 (2H, m),4.89-5.09 (2H, m), 6.70 (1H, brd, J=7.41z), 7.66 (1H, m); MS (FAB, POS)m/z: 434 (M+H)+.

(3) Preparation of(4R)-2-[(2R)-(2-acetylamino-2-methoxycarbonyl)ethylsulfonyl]methyl-4-tert-butyldimethylsiloxy-2-cyclopentan-1-one(Compound a)

Compound (a-2) (355 mg, 0.82 mmol) was dissolved in ethanol (20 ml) and10% Pd—C (80 mg, 50% hydrated) was added to the solution. The mixturewas stirred at room temperature for 5 hours in hydrogen atmosphere. Thereaction solution was filtered and the filtrate was concentrated to giveCompound (a) (330 mg, yield: 92.9%).

MS (FAB, POS) m/z: 436 (M+H)+.

(4) Preparation of (4R)-2-[(2R)-(2-acetylamino-2-carbonyl)ethylthio]methyl-4-tert-butyldimethylsiloxy-2-cyclopentan-1-one(Compound a-3)

Acetone (2 ml), methanol (8 ml), N-acetyl-L-cysteine (123.9 mg, 0.76mmol) and 1 N sodium hydroxide (1.52 ml) were added to Compound (a) (330mg, 0.76 mmol). The mixture was stirred at room temperature for 2 hours.After the reaction solution was concentrated, purification was performedusing Sephadex LH-20 (200 ml, 80% hydrated methanol) to give Compound(a-3) (299 mg). The compound was used for the subsequent reactionwithout further purification.

(5) Preparation of5-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-2-cyclopenten-1-one(Compound 1C)

Methanol (15 ml), water (1 ml) and Dowex 50 (H+ type, 300 mg) were addedto Compound (a-3) (299 mg, 0.76 mmol). The mixture was stirred at roomtemperature for 20 hours. After filtration, silica gel (1 g) was addedto the filtrate followed by concentration. The residue obtained waspurified by silica gel column chromatography (80 ml,dichloromethane:methanol:acetic acid=5:1:0.1) to give Compound (1C) (83mg, yield: 39%).

1H-NMR (200 MHz, D2O) δ: 2.00 (3H, s), 2.45-3.16 (7H, m), 4.52 (1H, m),6.20 (1H, m), 7.98 (1H, m); MS (FAB, POS) m/z: 258 (M+H)+.

EXAMPLE 19 Preparation of(4R)-2-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-hydroxy-2-cyclopenten-1-one(Compound 2C)

Acetone (2 ml), methanol (4 ml), N-acetyl-L-cysteine (61.9 mg, 0.39mmol) and 1 N sodium hydroxide (0.76 ml) were added to(4R)-2-[(2R)-(2-acetylamino-2-methoxycarbonyl)ethylsulfonyl]methyl-4-tert-butyldimethylsioloxy-2-cyclopenten-1-one(165 mg, 0.38 mmol). The mixture was stirred at room temperature for 2hours. After the reaction solution was concentrated, methanol (5 ml),water (1 ml) and Dowex 50 (H type, 700 mg) were added to the residuefollowed by stirring at room temperature for 16 hours. After filtration,silica gel (500 mg) was added to the reaction mixture, which was thenconcentrated. The residue was purified by silica gel columnchromatography (80 ml, dichloro-methane:methanol:acetic acid=5:1:0.1).After concentration, the residue was dissolved in water (10 ml) and 1Nsodium hydroxide was added thereto to adjust the pH to 6.9. Thus, thesodium salt (61 mg, yield: 54.4%) of Compound (2C) was obtained.

1H-NMR (200 MHz, D2O) δ: 2.00 (3H, s), 2.3 (1H, dd, J=1.83 Hz, 18.83Hz), 2.75-3.07 (3H, m), 3.32 (2H, s), 4.48 (1, dd, J=4.76 Hz, 8.01 Hz),4.98 (1H, m), 7.52 (1H, m); MS (ESI, NEG) m/z: 272 (M−Na)−.

EXAMPLE 20 Preparation of2-[(2R)-(2-acetylamino-2-carboxy)-ethylthio]methyl-3-hydroxy-2-cyclopenten-1-one(Compound 3C)

N-Acetyl-L-cysteine (193 mg, 1.18 mmol), methanol (2 ml), acetone (4 ml)and 1 N sodium hydroxide (2.36 ml) were added to Compound (d) (347 mg,1.18 mmol). The mixture was stirred at room temperature. 1N Sodiumhydroxide was added to the mixture portionwise until the reactionsolution became neutral (4 hours). Silica gel (1.2 g) was then added tothe reaction solution. The mixture was concentrated. The residue waspurified by silica gel column chromatography (100 ml,dichloromethane:methanol:acetic acid=5:1:0.1 to 2.5:1:0.1) to giveCompound (3C) (308 mg, yield: 95.6%).

1H-NMR (200 MHz, D2O) δ: 2.00 (1H, s), 2.49 (4H, s), 2.72-2.99 (2H, s),3.26 (2H, s), 4.38 (1H, dd, J=4.68 Hz, 8.26 Hz); MS (FAB, NEG) m/z: 272(M−H)−.

EXAMPLE 21 Preparation of3-{(2R)-2-acetylamino-2-carboxyethylthio}methyl-4-oxo-1-n-pentanoic acid(Compound 1D)

Compound (a) (256.3 mg, 2.00 mmols) was dissolved in tetrahydrofuran (3ml) and 1,8-diazabicyclo[5.4.0]-undeca-7-ene (609 mg, 4.00 mmols) wasadded to the solution. The mixture was reacted overnight at roomtemperature. After Amberlist-15 (3 g) was added to the reaction mixture,the mixture was stirred for 5 minutes. Then the resin was filtered off.The filtrate was concentrated in vacuo. The residue was purified bysilica gel column chromatography (40 ml, hexane:ethyl acetate=3:2 to1:1) to fractionate the fraction containing Compound (b). The fractionwas concentrated in vacuo. The residue obtained was dissolved intetrahydrofuran (3 ml). N-Acetyl-L-cysteine (107.7 mg, 0.66 mmol) andtriethylamine (265.1 mg, 2.62 mmols) were added to the solution. Afterstirring at room temperature overnight, the reaction solution wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography (40 ml, methylene chloride:methanol=10:1 to 2:1). Theobjective fraction was concentrated in vacuo and dissolved intetrahydrofuran (3 ml) and methanol (1 ml). Amberlist-15 (2 g) was addedto the solution. After stirring the mixture for 3 minutes, the resin wasfiltered off and the filtrate was concentrated in vacuo. The residue waspurified by silica gel column chromatography (40 ml, methylenechloride:methanol=10:1) to give Compound (1D) (40.9 mg, yield: 7%).

1H-NMR (200 MHz, DMSO-d6)) δ: 1.86 (3H, s), 2.18 (3H, s), 2.4-2.6 (2H,m), 2.7-3.0 (4H, m), 3.05 (1H, m), 4.38 (1H, ddd, J=8.1, 8.1, 5.1 Hz),8.24 (1H, d, J=8.1 Hz); MS (FAB, POS) m/z: 292 (M+H)+.

In a manner similar to the above procedures,3-{(2R)-2-acetylamino-2-methoxycarbonylethylthio}methyl-4-oxo-1-n-pentanoicacid (Compound 2D) may be prepared.

1H-NMR (200 MHz, DMSO-d6) δ: 1.86 (3H, s), 2.17 (3H, s), 2.4-2.7 (2H,m), 2.7-3.0 (4H, m), 3.04 (1H, m), 3.65 (3H, s), 4.46 (1H, ddd, J=8.1,8.1, 5.7 Hz), 8.39 (1H, d, J=8.1 Hz); MS (FAB, POS) m/z: 306 (M+H)+.

EXAMPLE 22 Preparation oftrans-2-{(2R)-2-acetylamino-2-methoxycarbonylethylthio}methyl-3-ethoxycarbonyl-1-cyclobutanone(Compound 3D)

(1) Preparation oftrans-2-hydroxymethyl-3-ethoxycarbonyl-1-cyclobutanone (Compound e-2)

Under ice cooling, diisopropylamine (0.296 g, 2.92 mmols) was added to asolution of n-butyl lithium (1.59 M/hexane solution, 2.79 mmols) intetrahydrofuran (8 ml) and the mixture was stirred for 10 minutes. Aftercooling to −78° C., a solution of 3-ethoxycarbonyl-1-cyclobutanone(Compound e-1) (355.4 mg, 2.50 mmols) in tetrahydrofuran (3 ml) wasdropwise added to the mixture, which was then stirred for 15 minutes.After the temperature was once elevated to 0° C., the mixture wasstirred for 15 minutes and again cooled to −78° C.Hexamethylphosphoramide (535.8 mg, 2.99 mmols) was added to the system.After stirring for 5 minutes, a solution obtained by trappingformaldehyde subjected to cracking at 160° C. and trapped in diethylether of −78° C. was poured into the system through a needle. Thereaction was terminated by adding hydrochloric acid and the insolublematters were filtered off. The filtrate was concentrated in vacuo. Theresidue was purified by silica gel column chromatography (50 ml,hexane:diethyl ether=1:1 to 1:2) to give Compound (e-2) (50.7 mg, yield:12%).

1H-NMR (60 MHz, CDCl3) δ: 1.30 (3H, t, J=7 Hz), 2.17 (1H, br), 3.23 (2H,m), 3.6-4.0 (4H, m), 4.20 (2H, q, J=7 Hz)

(2) Preparation of 2-methylidene-3-ethoxycarbonyl-1-cyclobutanone(Compound f)

Compound (e-2) was dissolved in methylene chloride (2 ml). Under icecooling, triethylamine (60.1 mg, 0.59 mmol) and mesyl chloride (36.7 mg,0.32 mmol) were added to the solution. The mixture was stirred for 30minutes under the same conditions. Water and diethyl ether were added tothe system for separation. The resulting organic layer was washed withwater and then with saturated sodium chloride aqueous solution, driedover anhydrous sodium sulfate and concentrated in vacuo to give Compound(f) (40.3 mg, yield: 96%).

1H-NMR (60 MHz, CDCl3) δ: 1.33 (3H, t, J=7 Hz), 3.30 (1H, dd, J=15 Hz, 8Hz), 3.40 (1H, dd, J=15.6 Hz), 4.00 (1H, m), 4.40 (2H, q, J=7 Hz), 5.50(1H, m), 6.03 (1H, m)

(3) Preparation oftrans-2-{(2R)-2-acetylamino-2-methoxycarbonylethylthio}methyl-3-ethoxycarbonyl-1-cyclobutanone(Compound 3D)

Compound (f) (40.3 mg, 0.26 mmol) was dissolved in methylene chloride (2ml). Under ice cooling, N-acetyl-L-cysteine (46.1 mg, 0.26 mmol) andtriethylamine (10.9 mg, 0.11 mmol) were added to the solution. Themixture was stirred for an hour under the same conditions. The reactionsolution was concentrated and the residue was purified by silica gelcolumn chromatography (20 ml, methylene chloride:methanol=40:1) andSephadex LH-20 (10 ml, eluted with methanol) to give Compound (3D) (27.4mg, yield: 36.4%).

1H-NMR (200 MHz, CDCl3) δ: 1.31 (3H, t, J=7.4 Hz), 2.07 (3H, s), 2.80(2H, m), 3.0-3.5 (5H, m), 3.78 (3H, s), 3.84 (1H, m), 4.24 (2H, dd,J=7.0, 1.7 Hz), 4.83 (1H, dt, J=7.6, 4.9 Hz), 6.46 (1H, brs, J=6.3 Hz);MS (FAB, POS) m/z: 332 (M+H)+.

EXAMPLE 23 Preparation oftrans-2-{(2R)-2-acetylamino-2-carboxyethylthio}methyl-3-oxo-1-cyclobutanecarboxylicAcid (Compound 4D)

After 3N hydrochloric acid aqueous solution (4 ml) was added to Compound(3) (17.4 mg, 0.05 mmol), the mixture was stirred at room temperatureovernight. The reaction solution was concentrated in vacuo. The residueobtained was purified twice by Sephadex LH-20 (100 ml and 200 ml, elutedwith methanol) and twice by silica gel column chromatography (2 ml,methylene chloride:methanol=20:1 to 2:1) to give Compound (4D) (6.0 mg,yield: 40%).

1H-NMR (200 MHz, CD3OD) δ: 2.01 (3H, 2.80-4.0 (8H, m), 4.60 (1H, m); MS(FAB, POS) m/z: 290 (M+H)+.

EXAMPLE 24 Preparation oftrans-3-acetoxymethyl-2-(2,3-dihydroxypropylthio)methyl-1-cyclobutanone(Compound 5D)

(1) Preparation of 3-acetoxymethyl-2-methylidene-1-cyclobutanone(Compound d)

After tetrahydrofuran (3 ml) and 1,8-diazabicyclo[5.4.0]-undeca-7-ene(25.5 mg, 0.168 mmol) was added to Compound (c) (30 mg, 0.14 mmol), themixture was stirred at room temperature for an hour. The reactionsolution was purified by silica gel column chromatography (10 ml,hexane:ethyl acetate=2:1) to give Compound (d) (23 mg, yield: 95.5%).

1H-NMR (60 MHz, CDCl3) δ: 2.00 (3H, s), 2.65-3.30 (3H, m), 4.33 (2H, m),5.30 (1H, d, J=4.1 Hz), 5.80 (1H, d, J=4.1 Hz)

(2) Preparation oftrans-3-acetoxymethyl-2-(2,3-dihydroxypropylthio)methyl-1-cyclobutanone(Compound 5D)

Compound (d) (23 mg, 0.133 mmol) was dissolved in acetone (1 ml) and asolution of alpha-thioglycerin (11 ul, 0.133 mmol) in methanol (1 ml)was added to the solution. The mixture was stirred at room temperaturefor an hour. The reaction solution was concentrated. The residueobtained was purified by silica gel column chromatography (20 ml,dichloromethane:methanol=20:1) to give Compound (5D) (19 mg, yield:51.3%).

1H-NMR (200 MHz, CDCl3) δ: 2.07, 2.10 (3H, sx2), 2.45-3.45 (8H, m), 3.503.90 (3H, m), 4.33 (2H, m)

EXAMPLE 24 Preparation of2-{(2R)-2-acetylamino-2-carboxy-ethylthio}methyl-3-oxo-1-cyclohexanecarboxylicacid (Compound 6D)

(1) Preparation of 4.5-dimethoxycarbonyl-3-trimethylsiloxy-1-cyclohexene(Compound g-3)

Compound (g-1) (589 mg, 4.09 mmols) and Compound (g-2) (588 mg, 4.09mmols) were dissolved in benzene. The reaction was carried out at 150°C. for 5 hours. After the reaction solution was concentrated, theresidue was purified by silica gel column chromatography (80 ml,hexane:ethyl acetate=5:1 to 3:1) to give Compound (g-3) (875 mg, yield:74.6%).

1H-NMR (200 MHz, CDCl3) δ: 0.05-0.12 (9H, m), 1.95-2.20 (1H, m),2.70-2.94 (1H, m), 2.95-3.19 (1H, m), 3.68 (3H, m), 3.70 (3H, s), 4.50(1H, m), 5.50-5.90 (2H, m)

(2) Preparation of 4,5-bis(hydroxymethyl)-3-hydroxy-1-cyclohexene(Compound a-4)

Lithium borohydride was suspended in anhydrous tetrahydrofuran (25 ml).Under ice cooling, a solution of Compound (g-3) (875 mg, 3.05 mmols) inanhydrous tetrahydrofuran (4 ml) was dropwise added to the suspension.The reaction was carried out for 2 hours. Then water (0.196 ml), 15%sodium hydroxide aqueous solution (0.196 ml) and water (0.59 ml) wereadded to the mixture. Stirring was further continued. After thesuspension was filtered, the filtrate was concentrated. The residue waspurified by silica gel column chromatography (20 ml, methylenechloride:methanol=20:1) to give Compound (g-4) (340 mg, 70.5%).

Preparation of 5,6-bis(hydroxymethyl)-2-cyclohexen-1-one (Compound g-5)

Compound (g-4) (320 mg, 2.02 mmols) was dissolved in acetone (20 ml).Manganese dioxide (1400 mg) was gradually added to the solution. Afterthe reaction, the precipitates were filtered off. The filtrate wasconcentrated and the residue was purified by silica gel columnchromatography (40 ml, methylene chloride:methanol=10:1) to giveCompound (g-5) (205 mg, 61.1%).

1H-NMR (200 MHz, CDCl3) δ: 2.30-2.60 (4H, m), 3.65 (2H, m), 3.76 (1H,dd, J=3.67 Hz, 11.08 Hz), 4.10 (1H, dd, J=3.67 Hz, 11.08 Hz), 5.98 (1H,dt, J=2.12 Hz, 12.13 Hz), 7.08 (1H, m)

(4) Preparation of 2,3-bis(acetoxymethyl)-1-cyclohexanone (Compound g-6)

Pyridine (10 ml) and acetic anhydride (3 ml) were added to Compound(g-5) (205 mg, 1.31 mmol). The mixture was reacted at room temperaturefor 2 hours. After the reaction solution was concentrated, the residuewas subjected to silica gel column chromatography (20 ml, hexane:ethylacetate=1:1). The fraction was concentrated and the concentrate wasdissolved in ethanol (20 ml). Palladium-carbon (50% hydrated) (50 mg)was added to the solution. The reaction was carried out at roomtemperature overnight in hydrogen atmosphere. The catalyst was filteredoff and the filtrate was concentrated. The residue was purified bysilica gel column chromatography (30 ml, methylenechloride:methanol=20:1) to give Compound (g-6) (175 mg, 73.0%).

1H-NMR (200 MHz, CDCl3) δ: 1.70 (2H, m), 1.89-2.20 (3H, m), 2.02 (3H,s), 2.08 (3H, s), 4.13 (2H, m), 4.38 (2H, m)

(5) Preparation of3-acetoxymethyl-2-[2,3-(dihydroxy)propylthio]methyl-1-cyclohexanone(Compound g-7)

2,3-Bis(acetoxymethyl)-1-cyclohexanone (Compound g-6) (200 mg, 0.826mmol) was dissolved in acetone (3 ml). A solution of alpha-thioglycerin(89.2 mg, 0.826 mmol) in methanol (1 ml) and 1N sodium hydroxide (0.826ml) were added to the solution. The mixture was stirred at roomtemperature for an hour. Silica gel (1 g) was added to the reactionmixture. After concentration, the residue was purified by silica gelcolumn chromatography (30 ml, dichloromethane:methanol=20:1) to giveCompound (g-7) (175 mg, yield: 73.0%).

MS (FAB, POS) m/z: 291 (M+H)+.

(6) Preparation of3-acetoxymethyl-2-[(2,3-O-isopropylidene)propylthio]methyl-1-cyclohexanone(Compound g-8)

Compound (g-7) (170 mg, 0.586 mmol) was dissolved in anhydrous acetone(1.5 ml). p-Toluenesulfonic acid monohydrate (11 mg, 0.06 mmol),dimethoxypropane (0.34 ml, 1.76 mmol) were added to the solution. Themixture was stirred at room temperature for 30 minutes. After water (2ml) was added to the reaction mixture and the pH was adjusted to 7.0with saturated hydrogensodium carbonate, the mixture was extracted threetimes with ethyl acetate (5 ml). The organic layer was washed withsaturated sodium chloride aqueous solution (5 ml), dried over anhydroussodium sulfate and concentrated to give Compound (g-8) (191 mg, yield:98.7%).

1H-NMR (200 MHz, CDCl3) δ: 1.30 (3H, s), 1.39 (3H, s), 1.52-2.15 (5H,m), 2.03 (3H, s), 2.20-3.05 (7H, m) 3.67 (1H, m), 3.82-4.29 (4H, m)

(7) Preparation of3-hydroxymethyl-2-[(2,3-O-isopropylidene)propylthio]methyl-1-cyclohexanone(Compound g-9)

Compound (g-8) (191 mg, 0.578 mmol) was dissolved in methanol (2 ml).Under ice cooling, water (0.2 ml) and 1N sodium hydroxide (0.57 ml) wereadded to the solution. The mixture was stirred for 15 minutes while icecooling. By adding 1N hydrochloric acid to the reaction mixture, the pHwas adjusted to 6.8. Silica gel (500 mg) was added to the system. Themixture was then concentrated and the residue was purified by silica gelcolumn chromatography (20 ml, dichloromethane:methanol=30:1) to giveCompound (g-9) (155 mg, yield: 93.1%).

MS (FAB, POS) m/z: 289 (M+H)+.

(8) Preparation of3-hydroxymethyl-2-[(2RS)-(2,3-O-isopropylidene)propylsulfonyl]methyl-1-cyclohexanone(Compound g-10)

Compound (g-9) (155 mg, 0.538 mmol) was dissolved in dichloromethane (2ml). Under ice cooling, a dichloromethane solution (5 ml) ofm-chloroperbenzoic acid (232 mg, purity 80%, 1.07 mmol) was added to thesolution. After the reaction mixture was filtered, water (4 ml) and 20%sodium hydrogen sulfite (0.17 ml) were added to the filtrate. Saturatedsodium hydrogen carbonate was added to the mixture until the pH of theaqueous layer became 7.0. After the aqueous layer was extracted twicewith dichloromethane (10 ml), the dichloromethane layer was washed withsaturated sodium chloride aqueous solution (15 ml), dried over anhydroussodium sulfate and concentrated. The residue was purified by silica gelcolumn chromatography (18 ml, hexane:ethyl acetate=1:3) to give Compound(g-10) (151 mg, yield: 87.7%).

MS (FAB, POS) m/z: 321 (M+H)+.

(9) Preparation of2-[(2,3-O-isopropylidene)-propylsulfonyl]methyl-3-oxo-1-cyclohexanecarboxylicacid (Compound g)

Compound (g-10) (151 mg, 0.47 mmol) was dissolved in acetone (9 ml).Jones reagent was added to the solution until the solution turnedorange. The mixture was stirred at room temperature for 10 minutes.Thereafter, 2-propanol was added to the reaction mixture until it turnedgreen. The mixture was concentrated and water (5 ml) was added to theconcentrate. The resulting solution was extracted 3 times withdichloromethane (5 ml). The dichloromethane layer was washed withsaturated sodium chloride aqueous solution (10 ml), dried over anhydroussodium sulfate and then concentrated to give Compound (g) (88.6 mg,yield: 56.4%).

MS (ESI, NEG) m/z: 333 (M−H)−.

(10) Preparation of2-{(2R)-2-acetylamino-2-carboxyethylthio}methyl-3-oxo-1-cyclohexanecarboxylicacid (Compound 6D)

Compound (g) (88.6 mg, 0.265 mmol) was dissolved in acetone (3 ml).N-Acetyl-L-cysteine (43.2 mg, 0.265 mmol), 1N sodium hydroxide (0.78 ml,0.795 mmol) and methanol (1 ml) were added to the solution. The mixturewas stirred for 2 hour at room temperature. After the pH of the mixturewas adjusted to 6.8 with 1N hydrochloric acid, the residue was purifiedby Sephadex LH-20 (200 ml, 80% hydrated methanol) to give the sodiumsalt (57.7 mg, yield: 60.3%) of Compound (6D).

1H-NMR (200 MHz, D2O) δ: 1.52-2.18 (4H, m), 2.00 (3H, s), 2.27-3.22 (8H,m), 4.28 (1H, dd, J=4.03 Hz, 8.34 Hz); MS (ESI, NEG) m/z: 361 (M−Na)−.

EXAMPLE 25 Preparation of3-[(2R)-(2-acetylamino-2-carboxy)ethylthio]methyl-4-oxo-4-phenylbutyricAcid (Compound 7D)

N-Acetyl-L-cysteine (39 mg, 0.24 mmol) and ethanol (4 ml) were added to4-oxo-3-(1-piperidinyl)methyl-4-phenylbutyric acid (66 mg, 0.24 mmol).The mixture was heated to reflux for 2 hours. After the reaction mixturewas concentrated in vacuo, water (5 ml) and ethyl acetate (8 ml) wereadded to the residue. The pH of the aqueous layer was adjusted to 2.0with 1N hydrochloric acid followed by liquid-liquid separation. Themixture was extracted twice with ethyl acetate (8 ml). The collectedethyl acetate layers were washed with saturated sodium chloride aqueoussolution (5 ml), dried over anhydrous sodium sulfate and thenconcentrated in vacuo. The residue was purified by silica gel columnchromatography (20 ml, chloroform methanol=20:1) to give Compound (7D)(45 mg, yield: 53.1%).

1H-NMR (60 MHz, CD3OD) δ: 2.19 (1.5H, s), 2.20 (1.5H, s), 2.50-3.30 (6H,m), 4.16 (1H, m), 4.58 (1H, m), 7.55 (3H, m), 8.00 (2H, m); MS (FAB,POS) m/z: 354 (M+H)+.

EXAMPLE 26 Preparation of3-[(2R)-(2-acetylamino-2-methoxycarbonyl)ethylthio]methyl-4-oxo-4-phenylbutyricAcid (Compound 8D)

N-Acetyl-L-cysteine methyl ester (66.3 mg, 0.37 mmol) and ethanol (4 ml)were successively added to 4-oxo-3-(1-piperidyl)methyl-4-phenylbutyricacid (103 mg, 0.37 mmol). The mixture was heated to reflux for an hour.The reaction mixture was purified in a manner similar to Example 25 togive Compound (8D) (116 mg, yield: 84.5%).

1H-NMR (60 MHz, CDCl3) δ: 2.01 (1.5H, s), 2.03 (1.5H, s), 2.48-3.16 (6H,m), 3.70 (1.5H, s), 3.73 (1H, s), 4.17 (1H, m), 4.85 (1H, m), 6.70 (1H,m), 7.52 (3H, m), 7.90 (2H, m); MS (FAB, POS) m/z: 368 (M+H)+.

EXAMPLE 27 Preparation of3-[(2R)-(2-acetylamino-2-methoxycarbonyl)ethylthio]methyl-4-(4-methoxyphenyl)-4-oxobutyricAcid (Compound 9D)

N-Acetyl-L-cysteine methyl ester (66.3 mg, 0.37 mmol) and ethanol (3 ml)were added to 4-(4-methoxyphenyl)-4-oxo-3-(1-piperidyl)methyl-butyricacid (109 mg, 0.37 mmol). The mixture was heated to reflux for 2 hours.Purification was performed in a manner similar to Example 25 to giveCompound (9D) (110 mg, yield: 73.4%).

1H-NMR (200 MHz, CDCl3) δ: 1.98 (1.5H, s), 2.05 (1.5H, s), 2.68 (2H, m),2.90 (4H, m), 3.69 (1.5H, s), 3.72 (1.5H, s), 3.89 (3H, s), 4.02 (1H,m), 4.80 (1H, m), 6.48-6.72 (1H, m), 6.98 (2H, d, J=8.92 Hz), 7.40 (1H,brs), 7.98 (2H, dd, J=3.3 Hz, 8.92 Hz); MS (FAB, POS) m/z: 398 (M+H)+.

EXAMPLE 28 Preparation of3-{2-(acetylamino)ethylthio}methyl-4-(4-methoxyphenyl)-4-oxobutyric Acid(Compound 10D)

N-Acetyl-L-cysteamine (45 mg, 0.37 mmol) and ethanol (3 ml) were addedto 4-(4-methoxyphenyl)-4-oxo-3-(1-piperidyl)methyl-4-phenylbutyric acid(109 mg, 0.37 mmol). The mixture was heated to reflux for 2 hours.Purification was performed in a manner similar to Example 25 to giveCompound (10D) (93 mg, yield: 72%).

1H-NMR (200 MHz, CDCl3) δ: 1.98 (1.5H, s), 2.58-2.76 (4H, m), 2.90 (2H,m), 3.39 (2H, m), 3.89 (3H, m), 4.07 (1H, m), 6.12 (1H, t, J=4.68 Hz),6.60 (1H, brs), 6.95 (2H, d, J=8.9 Hz), 7.98 (2H, d, J=8.9 Hz); MS (FAB,POS) m/z: 340 (M+H)+.

EXAMPLE 29 Preparation of3-{2-(acetylamino)ethylthio}methyl-4-oxo-4-phenylbutyric Acid (Compound11D)

N-Acetyl-L-cysteamine (45 mg, 0.37 mmol) and ethanol (3 ml) were addedto 4-oxo-4-phenyl-3-(1-piperidyl)methylbutyric acid (103 mg, 0.37 mmol).The mixture was heated to reflux for 2 hours. Purification was performedin a manner similar to Example 25 to give Compound (11D) (83 mg, yield:71.7%).

1H-NMR (200 MHz, CDCl3) δ: 1.97 (3H, s), 2.58-2.78 (4H, m), 2.90 (2H,m), 3.48 (2H, m), 4.11 (1H, m), 6.25 (1H, t, J=5.21 Hz), 7.50 (3H, m),7.98 (2H, m), 8.05 (1H, brs); MS (FAB, POS) m/z: 310 (M+H)+.

EXAMPLE 30 Preparation of3-{2-(acetylamino)ethylthio}methyl-4-(4-methylphenyl)-4-oxobutyric Acid(Compound 12D)

N-Acetyl-L-cysteamine (57 mg, 0.47 mmol) and ethanol (3 ml) were addedto 4-(4-methylphenyl)-4-oxo-3-(1-piperidyl)methylbutyric acid (131 mg,0.47 mmol). The mixture was heated to reflux. Purification was performedin a manner similar to Example 25 to give Compound (12D) (114 mg, yield:73.6%).

1H-NMR (60 MHz, CDCl3) 3 : 2.30 (3H, s), 2.70 (3H, s), 2.76-3.30 (4H,m), 3.30-4.15 (4H, m), 4.33 (1H, m), 6.70 (1H, t, J=6.0 Hz), 7.50 (2H,d, J=9.2 Hz), 7.80 (1H, brs), 8.16 (2H, d, J=9.2 Hz); MS (FAB, POS) m/z:382 (M+H)+.

EXAMPLE 31 Preparation of3-{(2R)-(2-acetylamino-2-methoxycarbonyl)ethylthio}methyl-4-(4-methylphenyl)-4-oxobutyricAcid (Compound 13D)

N-Acetyl-L-cysteine methyl ester (92 mg, 0.52 mmol) and ethanol (3 ml)were added to 4-(4-methylphenyl)-4-oxo-3-(1-piperidyl)methylbutyric acid(142 mg, 0.52 mmol). The mixture was heated to reflux for 2 hours.Purification was performed in a manner similar to Example 25 to giveCompound (13D) (126 mg, yield: 63.5%).

1H-NMR (60 MHz, CDCl3) δ: 2.30 (3H, s), 2.38 (1.5H, s), 2.80 (3H, s),2.98-3.60 (6H, m), 4.01 (1.5H, s), 4.10 (1.5H, s), 4.40 (1H, m), 5.14(1H, m), 7.02 (1H, m), 7.41 (1H, brs), 7.52 (2H, d, J=8.5 Hz), 8.17 (2H,d, J=8.5 Hz); MS (FAB, POS) m/z: 324 (M+H)+.

EXAMPLE 32 Preparation of3-[(2R)-(2-acetylamino-2-methoxycarbonyl)ethylthio]methyl-4-oxo-4-(3-pyridyl)butyricAcid (Compound 32D)

(1) Preparation of methyl 4-oxo-4-(3-pyridyl)butyrate (Compound 32D-A)

In nitrogen atmosphere, a solution of 3-pyridinecarboxyaldehyde (10.7 g,100 mmols) in anhydrous dimethylformamide (20 ml) was dropwise added toa solution of sodium cyanide (2.44 g, 50 mmols) at 30° C. in anhydrousdimethylformamide (80 ml) over 30 minutes. After stirring for 30minutes, a solution of methyl acrylate (8.6 g, 100 mmols) in anhydrousdimethylformamide (80 ml) was dropwise added to the reaction mixtureover an hour followed by stirring for 3 hours at 30° C. Acetic acid(0.66 ml) and water (30 ml) were added to the reaction solution. Afterstirring for 10 minutes, the mixture was concentrated in vacuo. Water(360 ml) and chloroform (300 ml×3) were added to the residue forseparation. The resultant organic phase was washed with saturated sodiumchloride aqueous solution (300 ml), dried over anhydrous sodium sulfateand concentrated in vacuo. The residue was purified by silica gel columnchromatography (650 ml, hexane:ethyl acetate=1:1-1:2) to give Compound(32D-A) (7.87 g, yield: 40.7%).

(2) Preparation of 4-oxo-4-(3-pyridyl)butyric acid (Compound 32D-B)

Compound (32D-A) (5.04 g, 26.11 mmols) was dissolved in methanol (60ml). After 1N sodium hydroxide aqueous solution (32 ml) was added to thesolution, the mixture was stirred for 3 hours at room temperature. Then,2N hydrochloric acid (16 ml) was added to the reaction mixture followedby concentration in vacuo. The residue was purified by silica gel columnchromatography (250 ml, chloroform:methanol:acetic acid=20:1:0.5) togive Compound (32D-B) (3.13 g, yield: 66.9%).

1H-NMR (200 MHz, CD3OD) δ: 2.72 (3H, t, J=6.5 Hz), 3.33 (3H, t, J=6.5Hz), 7.59 (1H, m), 8.42 (1H, m), 8.73 (1H, m), 9.14 (1H, m); MS (FAB,POS) m/z: 180 (M+H)+.

(3) Preparation of 4-oxo-4-(3-pyridyl)-3-(1-piperidyl)methylbutyric acid(Compound 32D-C)

Piperidine (140 mg, 1.64 mmol) and 37% formalin (0.133 ml, 1.64 mmol)were added to Compound (32D-B) (246 mg, 1.37 mmol). The mixture wasstirred at 100° C. for 2 hours. Silica gel (1.8 g) was added to thereaction solution. After concentration, the residue was purified bysilica gel column chromatography (30 ml, chloroform:methanol:aceticacid=10:1:0.5 to 10:5:3) to give Compound (32D-C) (300 mg, yield: 79%).

1H-NMR (200 MHz, CDCl3) δ: 1.45-1.80 (6H, m), 2.30-3.15 (8H, m), 4.28(1H, m), 7.46 (1H, dd, J=4.7 Hz, 8.0 Hz), 8.00 (1H, brs), 8.37 (1H, dt,J=2.0 Hz, 8.0 Hz), 8.78 (1H, dd, J=1.6 Hz, J=4.8 Hz), 9.28 (1H, d, J=1.6Hz)

(4) Preparation of3-[(2R)-(2-acetylamino-2-methoxycarbonyl)ethylthio]methyl-4-oxo-4-(3-pyridyl)butyricacid (Compound 32D)

N-Acetyl-L-cysteine methyl ester (96.2 mg, 0.54 mmol) was added to asolution of Compound (32D-C) (150 ml, 0.54 mmol) in ethanol (3 ml). Themixture was heated to reflux for 2 hours. The reaction mixture wasconcentrated. The residue was purified by silica gel columnchromatography (30 ml, chloroform:methanol:acetic acid=20:1:0.5) to giveCompound (32D) (89 mg, yield: 44.7%).

1H-NMR (200 MHz, CDCl3) δ: 1.98 (1.5H, s), 2.01 (1.5H, s), 2.70 (2H, m),2.93 (4H, m), 3.68 (1.5H, s), 3.71 (1.5H, s), 4.06 (1H, m), 4.79 (1H,m), 6.80 (1H, m), 7.20 (1H, m, NH), 7.49 (1H, m), 8.35 (1H, m), 8.75(1H, d, J=3.9 Hz), 9.24 (1H, s), 1.048 (1H, brs); MS (FAB, POS) m/z: 369(M+H)+.

EXAMPLE 33 Preparation of4-[(2R)-{(2-acetylamino-2-carboxy)-ethylthiol}]methyl-5-oxo-5-phenylpentanoicAcid (Compound 38D)

(1) Preparation of 4-(1-piperazinyl)methyl-5-oxo-5-phenylpentanoic acid(Compound 38D-A)

4-Benzoylbutyric acid (1000.9 mg, 5.21 mmols) was suspended in aformalin aqueous solution (507 mg, 6.25 mmols) and piperidine (532 mg,6.25 mmols). The reaction was carried out at 100° C. for 3 hours and ahalf. Piperidine (517 mg, 6.07 mmols) was added thereto and the mixturewas heated to 100° C. for further 3 hours. After air-cooling to roomtemperature, the reaction mixture was concentrated in vacuo. The residuewas purified by silica gel column chromatography (100 ml,dichloromethane:methanol=10:1 to 5:1) to give Compound (38D-A) (1500.8mg, yield: 99%).

1H-NMR (200 MHz, CDCl3) δ: 1.2-1.8 (8H, m), 2.10 (1H, m), 2.42 (1H, m),2.5-3.0 (4H, m), 3.16 (1H, dd, J=2.0 Hz, 12.7 Hz), 3.38 (4H, m), 3.16(1H, dd, J=2.0 Hz, 12.7 Hz), 3.38 (1H, dd, J=8.1 Hz, 12.5 Hz), 4.37 (1H,m), 7.2-7.4 (2H, m), 7.46 (1H, t, J=7.4 Hz), 8.41 (2H, d, J=7.2 Hz),9.30 (1H, br).

MS (FAB, POS) m/z: 290 (M+H)+.

(2) Preparation of4-[(2R)-{(2-acetylamino-2-carboxy)ethylthiol}]methyl-5-oxo-5-phenylpentanoicacid (Compound 38D)

Compound (38D-A) (576.0 mg, 1.99 mmol) and (R)-N-acetylcysteine (324.7mg, 1.99 mmol) were dissolved in ethanol (5 ml). The solution was heatedto reflux for 4 hours. After air-cooling, the mixture was concentratedin vacuo. The residue was purified by silica gel column chromatography(100 ml, chloroform:methanol=10:1 to 3:1) to give Compound (38D) (417.4mg, yield: 57%).

1H-NMR (200 MHz, DMSO-d6) δ: 1.7-2.0 (2H, m), 1.83 (3H, d, J=2 Hz), 2.20(2H, t, J=7.3 Hz), 2.6-3.0 (4H, m), 3.86 (1H, m), 4.33 (1H, dt, J=4.8Hz, 7.4 Hz), 7.5-7.7 (3H, m), 8.00 (2H, dd, J=7.0 Hz, 2.2 Hz), 8.09 (1H,d, J-7.3 Hz).

MS (FAB, NEG) m/z: 366 (M−H)+.

EXAMPLE 34 Preparation of (1R,2S)-2-[N-(panthoyl--alanylamido)ethylthio]methyl-3-oxo-1-cyclopentanecarboxylic Acid(Compound 1E)

A 100 ml aliquot of seed culture medium (2.0% glycerin, 1.0% glucose,0.5% soybean meal, 0.3% peptone, 0.5% yeast extract, 0.2% calciumcarbonate, 0.05% dipotassium phosphate and 0.05% magnesium sulfate; pH7.0) was charged in an rotary shaker Erlenmeyer flask of 500 ml volumeand sterilized at 120° C. for 20 minutes in an autoclave. One platinumloop of strain NA32176 (FERM P-16372) was inoculated to the medium andcultured at 27 C for 2 days at 220 rpm.

In main culture, a 100 ml aliquot of culture medium (1.0% glucose, 4.0%starch syrup, 1.0% corn steep liquor, 0.2% yeast extract, 1.0% glutenmeal, 0.00011% iron sulfate heptahydrate, 0.00064% copper sulfatepentahydrate, 0.00015% zinc sulfate heptahydrate, 0.00079% manganesechloride tetrahydrate, 0.0001% cobalt chloride and 0.2% calciumcarbonate; pH 7.0) was charged in a rotary shaker Erlenmeyer flask of500 ml volume, which had been sterilized at 120° C. for 20 minutes in anautoclave. One milliliter of the above seed culture broth was inoculatedto the main medium charged in the flask and cultured at 27° C. for 2days, at 220 rpm.

The cultured broth (10 L) was filtered in a conventional manner toseparate the filtrate and the mycelial cake.

After the pH was adjusted to 8 with 4N sodium hydroxide, the filtratewas applied to a DIAION HP-20 column (1 L), and then washed. Elution wasperformed by a linear gradient from water (2 L) to 80% methanol (2 L).After methanol was removed, the pH of the eluted fraction was adjustedto 2 with 1N hydrochloric acid. Extraction with n-butanol followed.

The n-butanol layer was concentrate in vacuo. The residue (491 mg) wasapplied to Sephadex LH-20 column chromatography (fai 3.5×90 cm, movingphase: methanol). The active fraction (267 mg) thus obtained wasdissolved in a mixture of ethyl acetate-water (1:1). The solution wasthen subjected to centrifugal liquid-liquid partition chromatography(volume of 250 ml, 1500 rpm, flow rate: 3 ml/min)—the lower phase of themixture was previously seed to operate as the fixing phase). Afterwashing with the upper phase liquid of the mixture, the active fractionwas reversely eluted by the lower phase to give the crude activesubstance (16 mg). The crude substance was purified by Sephadex LH-20column chromatography (fai 1.8×85 cm, moving phase:methanol) to giveNA32176A (Compound E) (13 mg).

The appearance, molecular weight, solubility, Rf value by ODS thin layerchromatography, UV absorption spectrum, IR absorption spectrum, ¹H-NMRspectrum and ¹³C-NMR spectrum of NA32176A (Compound 1E) purified asabove were determined. The physicochemical properties of NA32176A(Compound 1E) were found to be as described above.

EXAMPLE 35 Preparation of 4-oxo-4-phenyl-3-(1-piperidyl)-methylbutyricacid (Compound 1F)

Compound (1F) may be prepared by a known process, e.g., described in J.Chem. Soc. (C), 2308 (1967).

EXAMPLE 36 Preparation of4-(4-methylphenyl)-4-oxo-3-(1-piperidyl)methylbutyric Acid (Compound 2F)

Piperidine (1027 mg, 12.07 mmols) and 37% formaldehyde aqueous solution(0.98 ml, 12.07 mmols) were added to 4-(4-methylphenyl)-4-oxobutyricAcid (2320 mg, 12.07 mmols). The mixture was heated to becomehomogeneous. The reaction solution was then stirred at room temperaturefor 15 hours and concentrated in vacuo. The residue was purified bysilica gel column chromatography (chloroform:methanol=20:1 to 10:1) togive Compound (2F) (745 mg, yield: 22.6%).

1H-NMR (60 MHz, CDCl3) δ: 1.66-2.36 (6H, m), 2.50-3.05 (2H, m), 2.85(3H, s), 3.60 (2H, m), 4.70 (1H, m), 7.61 (2H, d, J=9.1 Hz), 8.30 (2H,d, J=9.1 Hz), 10.3 (1H, brs); MS (FAB, POS) m/z: 274 (M+H)+.

EXAMPLE 37 Preparation of4-(4-methoxyphenyl)-4-oxo-3-(1-piperidyl)methylbutyric Acid (Compound3F)

Piperidine (851 mg, 10 mmols) and 37% formaldehyde aqueous solution(0.81 ml, 10 mmols) were added to 4-(4-methoxyphenyl)-4-oxobutyric Acid(2080 mg, 10 mmols). The mixture was heated to become homogeneous. Thereaction solution was stirred at room temperature for 3 hours andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (250 ml, chloroform:methanol=20:1 to 10:1) to giveCompound (3F) (552 mg, yield: 19%).

1H-NMR (60 MHz, CDCl3) δ: 1.60-2.48 (6H, m), 2.66-3.30 (2H, m),3.16-3.50 (4H, m), 3.70 (3H, m), 4.33 (3H, m), 4.80 (1H, m), 7.35 (2H,d, J=9.5 Hz), 8.50 (2H, d, J=9.5 Hz), 11.40 (1H, brs); MS (FAB, POS)m/z: 290 (M+H)+.

EXAMPLE 38 Preparation of4-oxo-4-phenyl-3-(1-pyrrolidinyl)-methylbutyric acid (Compound 4F)

Pyrrolidine (1020 mg, 14.34 mmols) and 37% formaldehyde aqueous solution(1.16 ml) were added to 4-oxo-4-phenylbutyric acid (2555 mg, 14.34mmols). The mixture was heated to become homogeneous. The reactionsolution was stirred at room temperature for 10 hours and concentratedin vacuo. A part of the residue (920 mg) was purified by silica gelcolumn chromatography (90 ml, chloroform:methanol=5:1 to 2:1) to giveCompound (4F) (372 mg, yield: 40%).

1H-NMR (60 MHz, CD3OD) δ: 2.17 (4H, m), 2.64 (2H, m), 3.30-3.72 (6H, m),4.33 (1H, m), 7.60 (3H, m), 8.12 (2H, m); MS (FAB, POS) m/z: 262 (M+H)+.

EXAMPLE 39 Preparation of 3-(4-morpholinyl)methyl-4-oxo-4-phenylbutyricAcid (Compound 5F)

Morpholine (3891 mg, 4.47 mmols) and 37% formaldehyde solution (0.37 g,4.47 mmols) were added to 4-oxo-4-phenylbutyric acid (797 mg, 4.47mmols). The mixture was heated to become homogeneous. The reactionsolution was stirred at room temperature for 15 hours and concentratedin vacuo. The residue was purified by silica gel column chromatography(200 ml, chloroform:methanol=10:1 to 2:1) to give Compound (5F) (510 mg,yield: 41%).

1H-NMR (200 MHz, CD3CD) δ: 2.40-3.08 (8H, m), 3.69 (4H, t, J=4.68 Hz),4.21 (1H, m), 7.50 (3H, m), 8.00 (2H, m), 10.40 (1H, brs); MS (FAB, POS)m/z: 278 (M+H)+.

EXAMPLE 40 Preparation of3-f1-(4-methylpiperazinyl)}methyl-4-oxo-4-phenylbutyric Acid (Compound6F)

1-Methylpiperazine (349 mg, 3.51 mmols) and 37% formaldehyde solution(0.29 ml, 3.51 mmols) were added to 4-oxo-4-phenylbutyric acid (627 mg,3.51 mmols). The mixture was heated to become homogeneous. The reactionsolution was stirred at room temperature for 15 hours and concentratedin vacuo. The residue was purified by silica gel column chromatography(90 ml, butanol:acetic acid:water=20:1:1) and Sephadex LH-20 (250 ml,80% hydrated methanol) to give Compound (6F) (251 mg, yield: 24.6%).

1H-NMR (60 MHz, CDCl3) δ: 2.50-3.60 (12H, m), 2.84 (3H, s), 4.50 (1H,m), 7.80 (3H, m), 8.30 (2H, m), 12.16 (1H, brs); MS (FAB, POS) m/z: 291(M+H)+.

EXAMPLE 41 Preparation of 3-(diethylamino)methyl-4-oxo-4-phenylbutyricAcid (Compound 7F)

Diethylamine (300 mg, 4.10 mmols) and 37% formaldehyde solution (0.33ml) were added to 4-oxo-4-phenylbutyric acid (730 mg, 4.10 mmols). Themixture was heated to become homogeneous. The reaction solution wasstirred at room temperature for 16 hours and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (90 ml,chloroform:methanol=10:1 to 5:1) to give Compound (7F) (312 mg, yield:28.9%).

1H-NMR (60 MHz, CDCl3) δ: 1.90 (6H, t, J=6.8 Hz), 3.06-4.00 (8H, m),4.95 (1H, m), 8.20 (3H, m), 8.72 (2H, m), 11.70 (1H, brs); MS (FAB, POS)m/z: 264 (M+H)+.

EXAMPLE 42 Preparation of(1R,2R)-3-oxo-2-(1-piperidyl)methyl-1-cyclopentanecarboxylic Acid(Compound 8F)

(1R,2S)-2-[(2RS)-(2,3-O-isopropylidene)-propylsulfonyl]methyl-3-oxo-1-cyclopentanecarboxylicacid (205 mg, 0.64 mmol) was dissolved in acetone (3 ml). To thesolution, piperidine (55 mg, 0.64 mmol), methanol (2 ml) and 1N sodiumhydroxide (0.45 ml) were successively added. The mixture was stirred atroom temperature for 20 hours. The reaction solution was concentrated invacuo. The residue was purified by Sephadex LH-20 (250 ml, 80% hydratedmethanol) to give Compound (8F) (75 mg, yield: 52%).

MS (FAB, POS) m/z: 226 (M+H)+.

EXAMPLE 43 Preparation of4-oxo-4-(3-pyridyl)-3-(1-piperidyl)methylbutyric Acid (Compound 12F)

(1) Preparation of methyl 4-oxo-4-(3-pyridyl)butyrate (Compound 12F-A)

In nitrogen atmosphere, a solution of 3-pyridinecarboxyaldehyde (10.7 g,100 mmols) in anhydrous dimethylformamide (20 ml) was dropwise added toa solution of sodium cyanide (2.44 g, 50 mmols) at 30° C. in anhydrousdimethylformamide (80 ml) over 30 minutes. After stirring for 30minutes, a solution of methyl acrylate (8.6 g, 100 mmols) in anhydrousdimethylformamide (80 ml) was dropwise added to the reaction mixtureover an hour followed by stirring for 3 hours at 30° C. Acetic acid(0.66 ml) and water (30 ml) were added to the reaction solution. Afterstirring for 10 minutes, the mixture was concentrated in vacuo. Water(360 ml) and chloroform (300 ml×3) were added to the residue forseparation. The resultant organic phase was washed with saturated sodiumchloride aqueous solution (300 ml), dried over anhydrous sodium sulfateand concentrated in vacuo. The residue was purified by silica gel columnchromatography (650 ml, hexane:ethyl acetate=1:1-1:2) to give Compound(12F-A) (7.87 g, yield: 40.7%).

(2) Preparation of 4-oxo-4-(3-pyridyl)butyric acid (Compound 12F-B)

Compound (12F-A) (5.04 g, 26.11 mmols) was dissolved in methanol (60ml). After 1N sodium hydroxide aqueous solution (32 ml) was added to thesolution, the mixture was stirred for 3 hours at room temperature. Then,2N hydrochloric acid (16 ml) was added to the reaction mixture followedby concentration in vacuo. The residue was purified by silica gel columnchromatography (250 ml, chloroform:methanol:acetic acid=20:1:0.5) togive Compound (12F-B) (3.13 g, yield: 66.9%).

1H-NMR (200 MHz, CD3OD) δ: 2.72 (3H, t, J=6.5 Hz), 3.33 (3H, t, J=6.5Hz), 7.59 (1H, m), 8.42 (1H, m), 8.73 (1H, m), 9.14 (1H, m); MS (FAB,POS) m/z: 180 (M+H)+.

(3) Preparation of 4-oxo-4-(3-pyridyl)-3-(1-piperidyl)methylbutyric acid(Compound 12F

Piperidine (140 mg, 1.64 mmol) and 37% formalin (0.133 ml, 1.64 mmol)were added to Compound (12F-B) (246 mg, 1.37 mmol). The mixture wasstirred at 100° C. for 2 hours. Silica gel (1.8 g) was added to thereaction solution. After concentration, the residue was purified bysilica gel column chromatography (30 ml, chloroform:methanol:aceticacid=10:1:0.5 to 10:5:3) to give Compound (12F) (300 mg, yield: 79%).

1H-NMR (200 MHz, CDCl3) δ: 1.45-1.80 (6H, m), 2.30-3.15 (8H, m), 4.28(1H, m), 7.46 (1H, dd, J=4.7 Hz, 8.0 Hz), 8.00 (1H, brs), 8.37 (1H, dt,J=2.0 Hz, 8.0 Hz), 8.78 (1H, dd, J=1.6 Hz, J-4.8 Hz), 9.28 (1H, d, J=1.6Hz); MS (FAB, POS) m/z: 180 (M+H)+.

EXAMPLE 44 Preparation of 4-(2-furyl)-4-oxo-3-(1-piperidyl)methylbutyricAcid (Compound 26F)

(1) Preparation of methyl 4-(2-furyl)-4-oxobutyrate (Compound 26F-A)

After 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (1.0 g, 4mmols) and triethylamine (2.02 g, 20 mmols) were added to a solution offurfural (4.8 g, 50 mmols) in absolute ethanol (30 ml). The mixture wasstirred at room temperature for 40 minutes. Methyl acrylate (5.0 g, 50mmols) was further added to the mixture followed by heating to refluxfor 7 hours. The reaction solution was concentrated in vacuo. Theresidue obtained was purified by silica gel column chromatography (600ml, hexane:ethyl acetate=2:1) to give Compound (26F-A) (3430 mg, yield:37.6%).

1H-NMR (200 MHz, CDCl3) δ: 2.74 (2H, t, J=6.8 Hz), 3.18 (2H, t, J=6.8Hz), 6.54 (1H, dd, J=1.7 Hz, 3.6 Hz), 7.23 (1H, dd, J=0.7 Hz, 3.6 Hz),7.59 (1H, dd, J=0.7 Hz, 1.7 Hz); MS (FAB, POS) m/z: 180 (M+H)+.

(2) Preparation of 4-(2-furyl)-4-oxobutyric acid (Compound 26F-B)

To a solution of Compound (26F-A) (1820 mg, 10 mmols) in methanol (20ml) was added 1N sodium hydroxide aqueous solution (10.5 ml). Themixture was stirred at room temperature for 3 hours. After concentrationin vacuo, water (30 ml) and ethyl acetate (30 ml) were added to theresidue for separation. The pH of the aqueous phase was adjusted to 3.0with 2N hydrochloric acid aqueous solution followed by extraction withethyl acetate (30 ml×2). The organic phase was washed with saturatedsodium chloride aqueous solution (50 ml), dried over anhydrous sodiumsulfate and concentrated in vacuo to give Compound (26F-B) (1445 mg,yield: 86%).

1H-NMR (200 MHz, CDCl3) δ: 2.77 (2H, t, J=6.6 Hz), 3.17 (2H, t, J=6.6Hz), 6.55 (1H, dd, J=1.7 Hz, 3.7 Hz), 7.23 (1H, dd, J=0.7 Hz, 3.6 Hz),7.59 (1H, dd, J=0.7 Hz, 1.7 Hz); MS (FAB, POS) m/z: 168 (M+H)+.

(3) Preparation of 4-(2-furyl)-4-oxo-3-(1-piperidyl)methylbutyric acid(Compound 26F)

Piperidine (797 mg, 9.36 mmol) and 37% formalin (0.76 ml, 9.36 mmols)were added to Compound (26F-B) (1431 mg, 8.51 mmols). The mixture wasstirred at room temperature for 4 days. Silica gel (4.5 g) was added tothe reaction solution. After concentrated in vacuo, the residue waspurified by silica gel column chromatography (100 ml,chloroform:methanol:acetic acid=10:1:0.5 to 3:1:0.3) to give Compound(26F) (1325 mg, yield: 62.5%).

1H-NMR (200 MHz, CDCl3) δ: 1.56 (2H, m), 1.79 (4H, m), 2.48 (1H, dd,J=10.7 Hz, 15.5 Hz), 2.82 (5H, m), 3.16 (2H, d, J=6.2), 4.08 (1H, m),6.60 (1H, dd, J=1.7 Hz, 3.6 Hz), 7.49 (1H, d, J=3.6 Hz), 7.66 (1H, d,J=1.6 Hz), 10.7 Hz (1H, brs); MS (FAB, NEG) m/z: 264 (M−H)−.

EXAMPLE 45 Preparation of3-(1-piperidyl)methyl-4-oxo-4-(4′-trifluoromethylphenyl)butyric Acid(Compound 9F)

(1) Preparation of 4′-(trifluoromethyl)cinnamic acid (Compound 9F-A)

A mixture of 4′-(trifluoromethyl)acetophenone (2500.5 mg, 13.29 mmols)and glyoxylic acid monohydrate (1223.3 mg, 13.29 mmols) was reacted at95° C. for 1 hours while sucking through an aspirator. Glyoxylic acidmonohydrate (439.5 mg, 477 mole) was further added to the system and themixture was reacted at 95° C. for 2 h while sucking through oraspirator. After cooling to room temperature, 20 ml of 5% potassiumcarbonate was added to the reaction solution. The mixture was extractedtwice with ethyl acetate. Aqueous layer was adjusted to pH1 with 4Nhydrochloric acid and then extracted with ethylacetate twice. Theextract was washed with water and then saturated sodium chloride aqueoussolution, dried over anhydrous sodium sulfate and concentrated in vacuo.The residue was dissolved in acetic acid (10 ml) and conc. hydrochloricacid (0.5 ml) was added to the solution. The mixture was heated toreflux for 7 hours. The reaction solution was concentrated in vacuo. Theresidue was dissolved in ethyl acetate. The solution was washed withwater and then saturated sodium chloride aqueous solution, dried overanhydrous sodium sulfate and concentrated in vacuo. The residue wasrecrystallized from hexane-ethyl acetate to give Compound (9F-A) (1554.5mg, yield: 48%).

1H-NMR (60 MHz, CD3OD) δ: 6.93 (1H, d, J=15 Hz), 7.83 (2H, d, J=10 Hz),8.00 (1H, d, J=15 Hz), 8.14 (2H, d, J=10 Hz)

(2) Preparation of 4-(4′-(trifluoromethylphenyl)-butyric acid (Compound9F-B)

Compound (9F-A) (1036.9 mg, 4.25 mmols) was dissolved in acetic acid (9ml) and water (2 ml). Zinc powders (320.1 mg, 4.89 mmols) were added tothe solution. The mixture was stirred at room temperature for 4 hours.After filtering through celite, the filtrate was concentrated in vacuo.The residue was suspended in ethyl acetate and purified to give Compound(9F-B) (1111.0 mg, 100%).

1H-NMR (200 MHz, DMSO-d6) δ: 3.22 (2H, t, J=6.3 Hz), 3.37 (br), 7.88(2H, d, J=8.3 Hz), 8.15 (2H, d, J=8.3 Hz).

(3) Preparation of3-(1-piperidyl)methyl-4-oxo-4-(4′-trifluoromethylphenyl)butyric acid(Compound 9F)

Compound (9F-B) (1005.7 mg, 4.08 mmols) was dissolved indimethylsulfoxide (10 ml). Formalin aqueous solution (507 mg, 6.25mmols) and piperidine (532 mg, 6.25 mmols) was added to the solution.The mixture was reacted at 100° C. for 24 hours. After ice-cooling, theprecipitates were filtered off. The filtrate was separated with waterand ethyl acetate. After the aqueous phase was extracted with ethylacetate, the combined organic layers were washed with saturated sodiumchloride aqueous solution and concentrated in vacuo. The residue waspurified by silica gel column chromatography (200 ml, chloroformmethanol=5:1 to 1:2) to give Compound (9F) (312.5 mg, yield: 22%).

1H-NMR (200 MHz, DMSO-d6) δ: 1.4-1.0 (6H, m), 2.36 (1H, dd, J=10.1 Hz,15.2 Hz), 2.70 (1H, dd, J=15.3 Hz, 2.4 Hz), 2.7-3.0 (4H, m), 3.26 (2H,d, J=6.2 Hz), 4.40 (1H, m), 7.78 (2H, d, J=8.5 Hz), 8.24 (2H, d, J=8.1Hz). MS (FAB, NEG) m/z: 343 (M).

EXAMPLE 46 Preparation of2-methyl-4-oxo-4-phenyl-3-(1-piperazinyl)methylbutyric Acid (Compound41F)

2-Methyl-4-oxo-4-phenylbutyric acid (1000.5 mg, 5.21 mmols) wassuspended in formalin aqueous solution (507 mg, 6.25 mmols) andpiperidine (532 mg, 6.25 mmols). Ethanol (6 ml) was further added to thesuspension. The reaction was conducted at 100° C. for 40 minutes. Thecrystals obtained by filtration with heating were dried to give Compound(41F) (529.2 mg, yield: 35%).

MS (FAB, POS) m/z: 290 (M+H)+.

EXAMPLE 47 Preparation of4-(1-piperazinyl)methyl-5-oxo-5-phenylpentanoic Acid (Compound 42F)

4-Benzoylbutyric acid (1000.9 mg, 5.21 mmols) was suspended in aformalin aqueous solution (507 mg, 6.25 mmols) and piperidine (532 mg,6.25 mmols). The reaction was carried out at 100° C. for 3 hours and ahalf. Piperidine (517 mg, 6.07 mmols) was added thereto and the mixturewas heated to 100° C. for further 3 hours. After air-cooling to roomtemperature, the reaction mixture was concentrated in vacuo. The residuewas purified by silica gel column chromatography (100 ml,dichloromethane: L=10:1 to 5:1) to give Compound (42F) (1500.8 mg,yield: 99%).

1H-NMR (200 MHz, CdCl3) δ: 1.2-1.8 (8H, m), 2.10 (1H, m), 2.42 (1H, m),2.5-3.0 (4H, m), 3.16 (1H, dd, J=2.0 Hz, 12.7 Hz), 3.38 (1H, dd, J=8.1Hz, 12.5 Hz), 4.37 (1H, m), 7.2-7.4 (2H, m), 7.46 (1H, t, J=7.4 Hz),8.41 (2H, d, J=7.2 Hz), 9.30 (1H, br). MS (FAB, OOS) m/z: 290 (M+H)+.

Test Example 1

Neuron-like neurite extension effect of the compounds of this inventionon PC12 cells

The effect of the compounds of the invention was examined by amodification of the method of Green et al., Ann. Rev. Neurosci., 3, 353,1980, and evaluated in terms of morphological change of PC12 cells and alevel of the change. That is, PC12 cells were inoculated onDulbecco-modified Eagle's medium supplemented with 10% calf fetal serumand 10% equine serum in approximately 100,000 cells/ml. The cells wereincubated at 37° C. overnight in 5% CO₂ using collagen-coated 96 wellmultiplates. Morphological change of the cells was microscopicallyobserved one day after the test compound was added to each well underthis conditions.

The minimum effective dose (MED, g/ml) of each compound on PC12 cellsthat caused neuron-like neurite extension is shown in Table 2 below.

TABLE 2 Minimum effective dose to cause neuron-like neurite extension onPC12 cells Com- pound MED No. (g/ml)  1A 3.2  2A 3.2  6A 25  1B 3.2  2B1.6  3B 3.2  4B 3.2  5B 0.8  6B 1.6  7B 3.1  8B 0.8  9B 6.3 13B 1.6 14B3.1 15B 3.1  2C 6.3  1D 25  2D 13  3D 0.8  4D 13  5D 50  6D 50  7D 13 8D 6.3  9D 50 10D 100 11D 13 12D 13 13D 13 32D 3.1 38D 6.3  1E 1.2  1F1.6  2F 3.1  3F 3.1  4F 1.6  5F 3.1  6F 3.1  7F 1.6  8F 1.6 12F 3.1 26F3.1  9F 0.8 41F 6.3 42F 1.6

Industrial Applicability

The compounds of the present invention or pharmacologically acceptablesalts thereof exhibit a potent neuron differentiation acceleratingactivity. The pharmaceutical compositions comprising these compounds orpharmacologically acceptable salts thereof are thus useful as neurondifferentiation accelerators and effectively applicable as medicamentsfor the treatment of central or nervous system disorders.

What is claimed is:
 1. A ketone derivative of formula [1D]:

wherein: A_(D) is an unsubstituted or substituted aromatic hydrocarbon, heterocyclic ring or saturated heterocyclic ring; B_(D) is hydrogen or an unsubstituted aliphatic hydrocarbon group having 1 to 4 carbon atoms; X_(D) is O, S, SO, SO₂ or NH; Y_(D) is a substituted or unsubstituted aliphatic hydrocarbon group having 1 to 6 carbon atoms or a substituted or unsubstituted aromatic hydrocarbon group or monocyclic aromatic heterocyclic ring having 3 to 6 carbon atoms; Z_(D) is carboxy or a group derived therefrom, an unsubstituted or substituted alkyl or alkenyl having 1 to 4 carbon atoms; or a pharmacologically acceptable salt thereof.
 2. A ketone derivative of formula [1D] or a pharmacologically acceptable salt thereof, according to claim 1, wherein: A_(D) is an unsubstituted or substituted aromatic hydrocarbon, aromatic heterocyclic ring or saturated heterocyclic ring; B_(D) is hydrogen or an unsubstituted aliphatic hydrocarbon group having 1 to 4 carbon atoms; X_(D) is S, O or SO; Y_(D) is an aliphatic hydrocarbon group having 1 to 6 carbon atoms (wherein at least one hydrogen is substituted with carboxy or a group derived therefrom, amino or a group derived therefrom, or, hydroxy or a group derived therefrom; and, Z_(D) is carboxy or a group derived therefrom.
 3. A ketone derivative of formula [1D] or a pharmacologically acceptable salt thereof, according to claim 2, wherein: A_(D) is an unsubstituted benzene ring wherein, when substituted, 1 to 3 hydrogen atoms are substituted with an unsubstituted alkyl group having 1 to 4 carbon atoms, a halogen, an alkoxy having 1 to 4 carbon atoms, or trifluoromethyl; B_(D) is hydrogen or an aliphatic hydrocarbon group having 1 to 4 carbon atoms; X_(D) is S, O or SO; Y_(D) is an aliphatic hydrocarbon group having 1 to 6 carbon atoms (wherein at least one hydrogen is substituted with carboxy, COOR1 (wherein R1 is a substituted or unsubstituted alkyl or alkenyl having 1 to 4 carbon atoms), CONR2R3 (wherein each of R2 and R3, which may be the same or different and independently represents hydrogen or an unsubstituted or substituted alkyl having 1 to 4 carbon atoms), COW (wherein W is a heterocyclic ring which may be unsubstituted or substituted with carboxy or a group derived therefrom or, amino or a group derived therefrom), or NR4R5 (wherein each of R4 and R5, which may be the same or different, and independently represents hydrogen, an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms or, an unsubstituted or substituted acyl having 1 to 5 carbon atoms) and, Z_(D) is carboxy, COOR7 (wherein R7 is an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms), CONR8R9 (wherein each of R8 and R9, which may be the same or different and independently represents hydrogen or an unsubstituted or substituted alkyl having 1 to 4 carbon atoms).
 4. A ketone derivative of formula [1D] or a pharmacologically acceptable salt thereof, according to claim 3, wherein: A_(D) is an unsubstituted or substituted benzene ring, wherein, when substituted, 1 to 3 hydrogen atoms are substituted with methyl, methoxy, methoxycarbonyl, nitro, cyano, a halogen or trifluoromethyl; B_(D) is hydrogen or an alkyl having 1 to 4 carbon atoms; X_(D) is S; Y_(D) is an aliphatic hydrocarbon group having 1 to 6 carbon atoms (wherein at least two hydrogen atoms are substituted with carboxy, COOR1′ (wherein R1′ is an alkyl or alkenyl having 1 to 4 carbon atoms), NHCOR14 (wherein R14 is an alkyl having 1 to 4 carbon atoms which hydrogen may optionally be substituted with fluorine), hydroxy or OCOR15 (wherein R15 is an alkyl having 1 to 4 carbon atoms); Z_(D) is carboxy, COOR7′ (wherein R7′ is an alkyl having 1 to 4 carbon atoms) or CH₂OR10′ (wherein R10′ is hydrogen or an acyl having 1 to 5 carbon atoms).
 5. A ketone derivative of formula [1D] or a pharmacologically acceptable salt thereof, according to claim 4, wherein: A_(D) is an unsubstituted benzene ring or a benzene ring substituted with methyl or methoxy; B_(D) is hydrogen; X_(D) is S; Y_(D) is 2-acetylamino-2-carboxyethyl, 2-acetylamino-2-methoxycarbonylethyl or 2-acetylaminoethyl; and, Z_(D) is carboxy, methoxycarbonyl, acetoxymethyl or hydroxymethyl.
 6. A ketone derivative of formula [1D] or a pharmacologically acceptable salt thereof, according to claim 2, wherein: A_(D) is an unsubstituted or substituted aromatic heterocyclic ring; B_(D) is hydrogen or an aliphatic hydrocarbon group having 1 to 4 carbon atoms; X_(D) is S, O, or SO; Y_(D) is an aliphatic hydrocarbon group having 1 to 6 carbon atoms (wherein at least one hydrogen is substituted with carboxy, COOR1 (wherein R1 is a substituted or unsubstituted alkyl or alkenyl having 1 to 4 carbon atoms), CONR2R3 (wherein each of R2 and R3, which may be the same or different and independently represents hydrogen or an unsubstituted or substituted alkyl having 1 to 4 carbon atoms), COW (wherein W is a heterocyclic ring which may be unsubstituted or substituted with carboxy or a group derived therefrom or, amino or a group derived therefrom), or NR4R5 (wherein each of R4 and R5, which may be the same or different, and independently represents hydrogen, an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms or, an unsubstituted or substituted acyl having 1 to 5 carbon atoms) and, Z_(D) is carboxy, COOR7 (wherein R7 is an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms), CONR8R9 (wherein each of R8 and R9, which may be the same or different and independently represents hydrogen or an unsubstituted or substituted alkyl having 1 to 4 carbon atoms).
 7. A ketone derivative of formula [1D] or a pharmacologically acceptable salt thereof, according to claim 6, wherein: A_(D) is an unsubstituted aromatic heterocyclic ring; B_(D) is hydrogen or an alkyl having 1 to 4 carbon atoms; X_(D) is S; Y_(D) is an aliphatic hydrocarbon group having 1 to 6 carbon atoms (wherein at least two hydrogen atoms are substituted with carboxy, COOR1′ (wherein R1′ is an alkyl or alkenyl having 1 to 4 carbon atoms), NHCOR14 (wherein R14 is an alkyl having 1 to 4 carbon atoms which hydrogen may optionally be substituted with fluorine), hydroxy or OCOR15 (wherein R15 is an alkyl group having 1 to 4 carbon atoms); Z_(D) is carboxy, COOR7′ (wherein R7′ is an alkyl group having 1 to 4 carbon atoms) or CH₂OR10′ (wherein R10′ is hydrogen or an acyl having 1 to 5 carbon atoms).
 8. A ketone derivative of formula [1D] or a pharmacologically acceptable salt thereof, according to claim 7, wherein: A_(D) is 3-pyridyl; B_(D) is hydrogen; X_(D) is S; Y_(D) is 2-acetylamino-2-carboxyethyl, 2-acetylamino-2-methoxycarbonylethyl; and Z_(D) is carboxy.
 9. A pharmaceutical composition comprising as an effective ingredient a ketone derivative of formula [1D] according to claim 1 or a ketone derivative according to any one of claims 2 to 5 and 6 to 8, or a pharmacologically acceptable salt thereof.
 10. A composition for the treatment of central nervous disorders comprising as an effective ingredient a ketone derivative of formula [1D] according to claim 1 or a ketone derivative according to any one of claims 2 to 5 and 6 to 8, or a pharmacologically acceptable salt thereof.
 11. A composition for the treatment of peripheral nervous disorders comprising as an effective ingredient a ketone derivative of formula [1D] according to claim 1 or a ketone derivative according to any one of claims 2 to 5 and 6 to 8, or a pharmacologically acceptable salt thereof.
 12. A composition for the treatment of promoting nerve cell differentiation comprising as an effective ingredient a ketone derivative of formula [1D] according to claim 1 or a ketone derivative according to any one of claims 2 to 5 and 6 to 8, or a pharmacologically acceptable salt thereof. 